Ashley I. Bush

l‐3,4‐dihydroxyphenylalanine (l‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parki

Publisher: Wiley

Date: 28-03-2019

DOI: 10.1111/JNC.14676

Abstract: Treatment with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson's disease pathogenesis has raised concern about potentiation of oxidative stress by l-DOPA. The rate of DA quinone formation increases in the presence of excess redox-active iron (Fe), which is a pathological hallmark of Parkinson's disease. Conversely, l-DOPA has pH-dependent Fe-chelating properties, and may act to 'redox silence' Fe and partially allay DA autoxidation. We examined the effects of l-DOPA in three murine models of parkinsonian neurodegeneration: early-life Fe overexposure in wild-type mice, transgenic human (h)A53T mutant α-synuclein (α-syn) over-expression, and a combined 'multi-hit' model of Fe-overload in hA53T mice. We found that l-DOPA was neuroprotective and prevented age-related Fe accumulation in the substantia nigra pars compacta (SNc), similar to the mild-affinity Fe chelator clioquinol. Chronic l-DOPA treatment showed no evidence of increased oxidative stress in wild-type midbrain and normalized motor performance, when excess Fe was present. Similarly, l-DOPA also did not exacerbate protein oxidation levels in hA53T mice, with or without excess nigral Fe, and showed evidence of neuroprotection. The effects of l-DOPA in Fe-fed hA53T mice were somewhat muted, suggesting that Fe-chelation alone is insufficient to attenuate neuron loss in an animal model also recapitulating altered DA metabolism. In summary, we found no evidence in any of our model systems that l-DOPA treatment accentuated neurodegeneration, suggesting DA replacement therapy does not contribute to oxidative stress in the Parkinson's disease brain.

3-Hydroxykynurenine and 3-Hydroxyanthranilic Acid Generate Hydrogen Peroxide and Promote α-Crystallin Cross-Linking by Metal Ion Reduction

Publisher: American Chemical Society (ACS)

Date: 26-05-2000

DOI: 10.1021/BI992997S

Abstract: The kynurenine pathway catabolite 3-hydroxykynurenine (3HK) and redox-active metals such as copper and iron are implicated in cataractogenesis. Here we investigate the reaction of kynurenine pathway catabolites with copper and iron, as well as interactions with the major lenticular structural proteins, the alpha-crystallins. The o-aminophenol kynurenine catabolites 3HK and 3-hydroxyanthranilic acid (3HAA) reduced Cu(II)>Fe(III) to Cu(I) and Fe(II), respectively, whereas quinolinic acid and the nonphenolic kynurenine catabolites kynurenine and anthranilic acid did not reduce either metal. Both 3HK and 3HAA generated superoxide and hydrogen peroxide in a copper-dependent manner. In addition, 3HK and 3HAA fostered copper-dependent alpha-crystallin cross-linking. 3HK- or 3HAA-modifed alpha-crystallin showed enhanced redox activity in comparison to unmodified alpha-crystallin or ascorbate-modified alpha-crystallin. These data support the possibility that 3HK and 3HAA may be cofactors in the oxidative damage of proteins, such as alpha-crystallin, through interactions with redox-active metals and especially copper. These findings may have relevance for understanding cataractogenesis and other degenerative conditions in which the kynurenine pathway is activated.

Overcoming the Blood-Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases.

Publisher: Wiley

Date: 31-07-2018

DOI: 10.1002/ADMA.201801362

Abstract: Therapies directed toward the central nervous system remain difficult to translate into improved clinical outcomes. This is largely due to the blood-brain barrier (BBB), arguably the most tightly regulated interface in the human body, which routinely excludes most therapeutics. Advances in the engineering of nanomaterials and their application in biomedicine (i.e., nanomedicine) are enabling new strategies that have the potential to help improve our understanding and treatment of neurological diseases. Herein, the various mechanisms by which therapeutics can be delivered to the brain are examined and key challenges facing translation of this research from benchtop to bedside are highlighted. Following a contextual overview of the BBB anatomy and physiology in both healthy and diseased states, relevant therapeutic strategies for bypassing and crossing the BBB are discussed. The focus here is especially on nanomaterial-based drug delivery systems and the potential of these to overcome the biological challenges imposed by the BBB. Finally, disease-targeting strategies and clearance mechanisms are explored. The objective is to provide the erse range of researchers active in the field (e.g., material scientists, chemists, engineers, neuroscientists, and clinicians) with an easily accessible guide to the key opportunities and challenges currently facing the nanomaterial-mediated treatment of neurological diseases.

Bioactive poly(2-oxazoline)-based nanomaterials bearing arylalkylamine and benzamide motifs possess intrinsic radical trapping and anti-ferroptosis properties

Publisher: Royal Society of Chemistry (RSC)

Date: 2023

DOI: 10.1039/D2BM02087D

Abstract: Poly((2-methyl-2-oxazoline)-grad-(2-phenyl-2-oxazoline)) and core-crosslinked micelles thereof are capable of inhibiting ferroptosis, a non-apoptotic iron-induced cell death mechanism.

A Normalisation Framework For Quantitative Brain Imaging; Application to Quantitative Susceptibility Mapping

Publisher: IEEE

Date: 04-2017

DOI: 10.1109/ISBI.2017.7950477

Increasing Intracellular Bioavailable Copper Selectively Targets Prostate Cancer Cells

Publisher: American Chemical Society (ACS)

Date: 24-05-2013

DOI: 10.1021/CB400198P

Abstract: The therapeutic efficacy of two bis(thiosemicarbazonato) copper complexes, glyoxalbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(gtsm)] and diacetylbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(atsm)], for the treatment of prostate cancer was assessed in cell culture and animal models. Distinctively, copper dissociates intracellularly from Cu(II)(gtsm) but is retained by Cu(II)(atsm). We further demonstrated that intracellular H2gtsm [reduced Cu(II)(gtsm)] continues to redistribute copper into a bioavailable (exchangeable) pool. Both Cu(II)(gtsm) and Cu(II)(atsm) selectively kill transformed (hyperplastic and carcinoma) prostate cell lines but, importantly, do not affect the viability of primary prostate epithelial cells. Increasing extracellular copper concentrations enhanced the therapeutic capacity of both Cu(II)(gtsm) and Cu(II)(atsm), and their ligands (H2gtsm and H2atsm) were toxic only toward cancerous prostate cells when combined with copper. Treatment of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model with Cu(II)(gtsm) (2.5 mg/kg) significantly reduced prostate cancer burden (∼70%) and severity (grade), while treatment with Cu(II)(atsm) (30 mg/kg) was ineffective at the given dose. However, Cu(II)(gtsm) caused mild kidney toxicity in the mice, associated primarily with interstitial nephritis and luminal distention. Mechanistically, we demonstrated that Cu(II)(gtsm) inhibits proteasomal chymotrypsin-like activity, a feature further established as being common to copper-ionophores that increase intracellular bioavailable copper. We have demonstrated that increasing intracellular bioavailable copper can selectively kill cancerous prostate cells in vitro and in vivo and have revealed the potential for bis(thiosemicarbazone) copper complexes to be developed as therapeutics for prostate cancer.

Systematic Review: Quantitative Susceptibility Mapping (QSM) of Brain Iron Profile in Neurodegenerative Diseases

Publisher: Frontiers Media SA

Date: 18-02-2021

DOI: 10.3389/FNINS.2021.618435

Abstract: Iron has been increasingly implicated in the pathology of neurodegenerative diseases. In the past decade, development of the new magnetic resonance imaging technique, quantitative susceptibility mapping (QSM), has enabled for the more comprehensive investigation of iron distribution in the brain. The aim of this systematic review was to provide a synthesis of the findings from existing QSM studies in neurodegenerative diseases. We identified 80 records by searching MEDLINE, Embase, Scopus, and PsycInfo databases. The disorders investigated in these studies included Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, Huntington's disease, Friedreich's ataxia, spinocerebellar ataxia, Fabry disease, myotonic dystrophy, pantothenate-kinase-associated neurodegeneration, and mitochondrial membrane protein-associated neurodegeneration. As a general pattern, QSM revealed increased magnetic susceptibility (suggestive of increased iron content) in the brain regions associated with the pathology of each disorder, such as the amygdala and caudate nucleus in Alzheimer's disease, the substantia nigra in Parkinson's disease, motor cortex in amyotrophic lateral sclerosis, basal ganglia in Huntington's disease, and cerebellar dentate nucleus in Friedreich's ataxia. Furthermore, the increased magnetic susceptibility correlated with disease duration and severity of clinical features in some disorders. Although the number of studies is still limited in most of the neurodegenerative diseases, the existing evidence suggests that QSM can be a promising tool in the investigation of neurodegeneration.

Alterations in Brain Transition Metals in Huntington Disease

Publisher: American Medical Association (AMA)

Date: 07-2001

DOI: 10.1001/ARCHNEUROL.2011.2945

Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration

Publisher: Elsevier BV

Date: 03-2019

DOI: 10.1016/J.FREERADBIOMED.2018.09.033

Abstract: Perturbations in iron homeostasis and iron accumulation feature in several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Proteins such as α-synuclein, tau and amyloid precursor protein that are pathologically associated with neurodegeneration are involved in molecular crosstalk with iron homeostatic proteins. Quantitative susceptibility mapping, an MRI based non-invasive technique, offers proximal evaluations of iron load in regions of the brain and powerfully predicts cognitive decline. Further, small molecules that target elevated iron have shown promise against PD and AD in preclinical studies and clinical trials. Despite these strong links between altered iron homeostasis and neurodegeneration the molecular biology to describe the association between enhanced iron levels and neuron death, synaptic impairment and cognitive decline is ill defined. In this review we discuss the current understanding of brain iron homeostasis and how it may be perturbed under pathological conditions. Further, we explore the ramifications of a novel cell death pathway called ferroptosis that has provided a fresh impetus to the "metal hypothesis" of neurodegeneration. While lipid peroxidation plays a central role in the execution of this cell death modality the removal of iron through chelation or genetic modifications appears to extinguish the ferroptotic pathway. Conversely, tissues that harbour elevated iron may be predisposed to ferroptotic damage. These emerging findings are of relevance to neurodegeneration where ferroptotic signalling may offer new targets to mitigate cell death and dysfunction.

Chronic Exposure to High Levels of Zinc or Copper has Little Effect on Brain Metal Homeostasis or A beta Accumulation in Transgenic APP-C100 Mice

Publisher: Springer Science and Business Media LLC

Date: 21-04-2009

DOI: 10.1007/S10571-009-9401-7

Abstract: Aberrant metal homeostasis may enhance the formation of reactive oxygen species and Abeta oligomerization and may therefore be a contributing factor in Alzheimer's disease. This study investigated the effect of chronic high intake of dietary Zn or Cu on brain metal levels and the accumulation and solubility of Abeta in vivo, using a transgenic mouse model that over expresses the C-terminal containing Abeta fragment of human amyloid precursor protein but does not develop amyloid deposits. Exposure to chronic high Zn or Cu in the drinking water resulted in only slight elevations of the respective metals in the brain. Total Abeta levels were unchanged although soluble Abeta levels were slightly decreased, without visible plaque formation, enhanced gliosis, antioxidant upregulation or neuronal loss. This study indicates that brain metal levels are only marginally altered by long term oral exposure to extremely high Cu or Zn levels, and that this does not induce Abeta-amyloid formation in human Abeta expressing, amyloid-free mice, although this is sufficient to modulate Abeta solubility in vivo.

Editorial: The CB2 cannabinoid system: A new strategy in neurodegenerative disorder and neuroinflammation

Publisher: Frontiers Media SA

Date: 06-04-2017

DOI: 10.3389/FNINS.2017.00196

Metal-protein attenuating compounds and Alzheimers disease

Publisher: Informa Healthcare

Date: 12-2004

DOI: 10.1517/13543784.13.12.1585

Abstract: Since the description of the amyloid plaque in the pathology of Alzheimer's disease, one of the main focuses of research has been the role of the amyloid precursor protein metabolite amyloid-beta, which is the constituent protein of plaque. Affecting the production, aggregation or clearance of this protein may well have a modifying effect on disease progression. Although available therapies for Alzheimer's disease may interact with amyloid-beta in vivo, no conspicuous disease-modifying effect has been demonstrated in clinical trials with these drugs. Drugs whose primary target is not the rectification of the neurotransmitter deficits associated with Alzheimer's disease but rather the life cycle of amyloid-beta are currently being developed with varying degrees of success. Of these drugs, the metal-protein attenuating compounds have currently the most encouraging clinical data supporting their use. Clioquinol is an ex le from this class, which has recently shown encouraging efficacy from early clinical evaluation in the absence of any compelling evidence of subacute myelopathic optic neuritis, which has been associated with this drug's use in Japanese populations. This article will discuss the scientific rationale behind the use of metal-protein attenuating compounds in Alzheimer's disease and summarise the available clinical trial data.

Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies

Publisher: American Physiological Society

Date: 03-2008

DOI: 10.1152/AJPCELL.00541.2007

Abstract: To understand the mechanisms of neuronal Zn 2+ homeostasis better, experimental data obtained from cultured cortical neurons were used to inform a series of increasingly complex computational models. Total metals (inductively coupled plasma-mass spectrometry), resting metallothionein, 65 Zn 2+ uptake and release, and intracellular free Zn 2+ levels using ZnAF-2F were determined before and after neurons were exposed to increased Zn 2+ , either with or without the addition of a Zn 2+ ionophore (pyrithione) or metal chelators [EDTA, clioquinol (CQ), and N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine]. Three models were tested for the ability to match intracellular free Zn 2+ transients and total Zn 2+ content observed under these conditions. Only a model that incorporated a muffler with high affinity for Zn 2+ , trafficking Zn 2+ to intracellular storage sites, was able to reproduce the experimental results, both qualitatively and quantitatively. This “muffler model” estimated the resting intracellular free Zn 2+ concentration to be 1.07 nM. If metallothionein were to function as the exclusive cytosolic Zn 2+ muffler, the muffler model predicts that the cellular concentration required to match experimental data is greater than the measured resting concentration of metallothionein. Thus Zn 2+ buffering in resting cultured neurons requires additional high-affinity cytosolic metal binding moieties. Added CQ, as low as 1 μM, was shown to selectively increase Zn 2+ influx. Simulations reproduced these data by modeling CQ as an ionophore. We conclude that maintenance of neuronal Zn 2+ homeostasis, when challenged with Zn 2+ loads, relies heavily on the function of a high-affinity muffler, the characteristics of which can be effectively studied with computational models.

Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis

Publisher: Springer Science and Business Media LLC

Date: 02-12-2021

DOI: 10.1038/S41418-021-00910-Z

Metal homeostasis in Alzheimer's disease

Publisher: Informa UK Limited

Date: 05-2006

DOI: 10.1586/14737175.6.5.711

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal dysfunction and the formation of amyloid plaques in the brain. Although the pathological processes resulting in the onset and progression of AD are not well understood, there is a growing body of evidence to support a central role for biometals in many critical aspects of the illness. Recent reports have described the exciting development of potential therapeutic agents based on the modulation of metal bioavailability. The metal ligand, clioquinol has demonstrated promising results in animal models and small clinical trials and a new generation of metal ligand-based therapeutics are currently under development. However, further research is necessary to fully understand the complex and interdependent pathways of biometal homeostasis and amyloid metabolism in AD. This information will be vital for the development of safe and effective metal-based pharmaceuticals for the treatment of AD and, potentially, other neurodegenerative disorders.

Copper transport into the secretory pathway is regulated by oxygen in macrophages

Publisher: The Company of Biologists

Date: 05-2009

DOI: 10.1242/JCS.043216

Abstract: Copper is an essential nutrient for a variety of biochemical processes however, the redox properties of copper also make it potentially toxic in the free form. Consequently, the uptake and intracellular distribution of this metal is strictly regulated. This raises the issue of whether specific pathophysiological conditions can promote adaptive changes in intracellular copper distribution. In this study, we demonstrate that oxygen limitation promotes a series of striking alterations in copper homeostasis in RAW264.7 macrophage cells. Hypoxia was found to stimulate copper uptake and to increase the expression of the copper importer, CTR1. This resulted in increased copper delivery to the ATP7A copper transporter and copper-dependent trafficking of ATP7A to cytoplasmic vesicles. Significantly, the ATP7A protein was required to deliver copper into the secretory pathway to ceruloplasmin, a secreted copperdependent enzyme, the expression and activity of which were stimulated by hypoxia. However, the activities of the alternative targets of intracellular copper delivery, superoxide dismutase and cytochrome c oxidase, were markedly reduced in response to hypoxia. Collectively, these findings demonstrate that copper delivery into the biosynthetic secretory pathway is regulated by oxygen availability in macrophages by a selective increase in copper transport involving ATP7A.

The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease

Publisher: Wiley

Date: 06-07-2007

DOI: 10.1111/J.1742-4658.2007.05918.X

Abstract: The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.

Benefits of adjunctive N-acetylcysteine in a sub-group of clozapine-treated individuals diagnosed with schizophrenia

Publisher: Elsevier BV

Date: 12-2015

DOI: 10.1016/J.PSYCHRES.2015.10.037

Ferroptosis and NRF2: an emerging battlefield in the neurodegeneration of Alzheimer's disease

Publisher: Portland Press Ltd.

Date: 12-2021

DOI: 10.1042/EBC20210017

Abstract: Ferroptosis is an iron- and lipid peroxidation-dependent cell death modality and emerging evidence indicates that ferroptosis has great explanatory potential for neuronal loss and associated CNS dysfunction in a range of neurodegenerative diseases (e.g., Alzheimer's, Parkinson's and Huntington's diseases, Motor neuron disease, Friedreich ataxia (FRDA)). Ferroptotic death results from lethal levels of phospholipid hydroperoxides that are generated by iron-dependent peroxidation of polyunsaturated fatty acids (PUFAs), such as arachidonic and adrenic acids, which are conjugated to specific phospholipids (e.g., phosphatidylethanolamines (PEs)). The major cellular protector against ferroptosis is glutathione peroxidase 4 (GPX4), a membrane-associated selenoenzyme that reduces deleterious phospholipid hydroperoxides to their corresponding benign phospholipid alcohols in a glutathione-dependent manner. Other complementary protective systems have also been identified that act to bolster cellular defences against ferroptosis. Many pharmacological modulators of the ferroptosis pathway have been identified, targeting proteins involved in iron homoeostasis and autophagy the production and detoxification of lipid peroxides, and cyst(e)ine/glutathione metabolism. While a growing number of cell signalling pathways converge to regulate the ferroptosis cascade, an emerging understanding of ferroptosis regulation suggests that the ferroptotic ‘tone’ of cells can be set by the transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), which transcriptionally controls many key components of the ferroptosis pathway. In this review, we provide a critical overview of the relationship between ferroptosis and NRF2 signalling. With a focus on the role of ferroptosis in Alzheimer's disease (AD), we discuss how therapeutic modulation of the NRF2 pathway is a viable strategy to explore in the treatment of ferroptosis-driven neurodegeneration.

Intracellular amyloid formation in muscle cells of A-transgenic Caenorhabditis elegans: Determinants and physiological role in copper detoxification

Publisher: Springer Science and Business Media LLC

Date: 06-01-2009

DOI: 10.1186/1750-1326-4-2

Abstract: The amyloid β-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine Aβ aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that Aβ is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that Aβ is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly. In the present work, we found that intracellular Aβ aggregation in muscle cells of Caenorhabditis elegans overexpressing Aβ peptide is affected by two single amino acid substitutions, E22G (Arctic) and V18A (NIC). Both variations show decrease intracellular amyloidogenesis compared to wild type Aβ. We show that intracellular amyloid aggregation of wild type Aβ is accelerated by Cu 2+ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that Aβ-transgenic worms display a higher tolerance to Cu 2+ toxic effects and that this resistance may be linked to the formation of amyloid aggregates. Our data show that intracellular Aβ amyloid aggregates may trap excess of free Cu 2+ buffering its cytotoxic effects and that accelerated intracellular Aβ aggregation may be part of a cell protective mechanism.

Cognitive gene risk profile for the prediction of cognitive decline in presymptomatic Alzheimer’s disease

Publisher: Elsevier BV

Date: 03-2018

DOI: 10.1016/J.PMIP.2018.03.001

The role of metal ions in neurology. An introduction

Publisher: Wiley

Date: 24-03-2006

DOI: 10.1002/0470028114.CH1

Beta-amyloid cuproprotein: a therapeutic target for alzheimer's disease

Publisher: Elsevier BV

Date: 07-2003

DOI: 10.1016/S0162-0134(03)80478-6

Metals in Alzheimer's and Parkinson's Diseases

Publisher: Elsevier BV

Date: 04-2008

DOI: 10.1016/J.CBPA.2008.02.019

Abstract: There has been steadily growing interest in the participation of metal ions (especially, zinc, copper, and iron) in neurobiological processes, such as the regulation of synaptic transmission. Recent descriptions of the release of zinc and copper in the cortical glutamatergic synapse, and influencing the response of the NMDA receptor underscore the relevance of understanding the inorganic milieu of the synapse to neuroscience. Additionally, major neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, are characterized by elevated tissue iron, and miscompartmentalization of copper and zinc (e.g. accumulation in amyloid). Increasingly sophisticated medicinal chemistry approaches, which correct these metal abnormalities without causing systemic disturbance of these essential minerals, are being tested. These small molecules show promise of being disease-modifying.

A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania

Publisher: SAGE Publications

Date: 14-03-2013

DOI: 10.1177/0004867413481631

Abstract: Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC). This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period. Fifteen participants were available for this report two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint. Although the s le size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.

Trial of Deferiprone in Parkinson’s Disease

Publisher: Massachusetts Medical Society

Date: 12-2022

DOI: 10.1056/NEJMOA2209254

Correction: Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C5SC90051D

Abstract: Correction for 'Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging' by Bence Paul et al. , Chem. Sci. , 2015, DOI: 10.1039/c5sc02231b.

Glutaredoxins employ parallel monothiol–dithiol mechanisms to catalyze thiol–disulfide exchanges with protein disulfides

Publisher: Royal Society of Chemistry (RSC)

Date: 2018

DOI: 10.1039/C7SC04416J

Abstract: Glutaredoxins were demonstrated to be a family of versatile enzymes capable of catalyzing thiol–disulfide exchange involving GSSG/GSH via different catalytic routes either alone or in parallel.

Adrenergic β receptor activation in the basolateral amygdala, which is intracellular Zn²⁺-dependent, rescues amyloid β1-42-induced attenuation of dentate gyrus LTP

Publisher: Elsevier BV

Date: 11-2018

DOI: 10.1016/J.NEUINT.2018.07.005

Abstract: On the basis of the evidence that the basolateral amygdala (BLA) modulates hippoc al memory processes via synaptic plasticity, here we report that adrenergic β receptor activation in the BLA rescues amyloid β

Metalloregulation of Protein Clearance: New Therapeutic Avenues for Neurodegenerative Diseases

Publisher: Elsevier

Date: 2017

DOI: 10.1016/B978-0-12-804562-6.00018-X

Meet our editorial board member

Publisher: Bentham Science Publishers Ltd.

Date: 19-10-2015

DOI: 10.2174/156720501209151019104454

Microglial ferroptotic stress causes non-cell autonomous neuronal death

Publisher: Cold Spring Harbor Laboratory

Date: 29-04-2022

DOI: 10.1101/2022.04.28.489869

Abstract: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). Finally, we utilised the SOD1 G37R mouse model of ALS and a novel CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo . We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Moreover, a molecular correlation between ferroptosis and neurotoxic astrocytes evident in ALS-affected spinal cord is recapitulated in the SOD1 G37R mouse model where treatment with the novel, CNS-permeant ferroptosis inhibitor, Cu II (atsm), ameliorated these markers and was neuroprotective. By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.

Model studies of cholesterol and ascorbate oxidation by copper complexes: Relevance to Alzheimer's disease β-amyloid metallochemistry

Publisher: Elsevier BV

Date: 12-2005

DOI: 10.1016/J.JINORGBIO.2005.09.011

Abstract: The neurotoxicity of the amyloid-beta peptide (Abeta) is causally linked to Alzheimer's disease (AD) and may be related to the redox chemistry associated with its interactions with copper ions and cholesterol in brain tissue. We have used density functional theory (DFT) calculations to study the mechanism controlling the Abeta/Cu catalyzed oxidation reactions of cholesterol and ascorbate using a model system. The computed results based on a binuclear Cu complex predict that oxidation of cholesterol (yielding 4-cholesten-3-one as a specific product) proceeds at a slow rate when catalyzed by a Abeta/Cu(II)|His-|Cu(II)/Abeta) aggregate. The computed results also suggest that monomeric Abeta/Cu(II) is not able to oxidize cholesterol. DFT also predicted that Abeta will cross-link via covalent dityrosine formation during the oxidation of ascorbate but not during the oxidation of cholesterol. Experimental data were consistent with these predictions.

Pharmacotherapeutic targets in Alzheimer's disease

Publisher: Wiley

Date: 18-11-2009

DOI: 10.1111/J.1582-4934.2008.00595.X

Connecting copper and cancer: from transition metal signalling to metalloplasia

Publisher: Springer Science and Business Media LLC

Date: 11-11-2021

DOI: 10.1038/S41568-021-00417-2

A comparison of ceruloplasmin to biological polyanions in promoting the oxidation of Fe2+ under physiologically relevant conditions

Publisher: Elsevier BV

Date: 12-2014

DOI: 10.1016/J.BBAGEN.2014.08.006

Abstract: Iron oxidation is thought to be predominantly handled enzymatically in the body, to minimize spontaneous combustion with oxygen and to facilitate cellular iron export by loading transferrin. This process may be impaired in disease, and requires more accurate analytical assays to interrogate enzymatic- and auto-oxidation within a physiologically relevant environment. A new triplex ferroxidase activity assay has been developed that overcomes the previous assay limitations of measuring iron oxidation at a physiologically relevant pH and salinity. Revised enzymatic kinetics for ceruloplasmin (Vmax≈35μMFe(3+)/min/μM Km≈15μM) are provided under physiological conditions, and inhibition by sodium azide (Ki for Ferric Gain 78.3μM, Ki for transferrin loading 8.1×10(4)μM) is quantified. We also used this assay to characterize the non-enzymatic oxidation of iron that proceeded linearly under physiological conditions. These findings indicate that the requirement of an enzyme to oxidize iron may only be necessary under conditions of adverse pH or anionic strength, for ex le from hypoxia. In a normal physiological environment, Fe(3+) incorporation into transferrin would be sufficiently enabled by the biological polyanions that are prevalent within extracellular fluids.

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression

Publisher: Springer Science and Business Media LLC

Date: 21-07-2022

DOI: 10.1007/S13311-022-01257-0

Abstract: Depressed in iduals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala.

A blood-based predictor for neocortical Aβ burden in Alzheimer's disease: results from the AIBL study

Publisher: Springer Science and Business Media LLC

Date: 30-04-2013

DOI: 10.1038/MP.2013.40

Abstract: Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aβ (extracellular β-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aβ accumulation, therefore, providing a platform for developing a population-based screen.

S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

Publisher: American Society for Clinical Investigation

Date: 06-11-2017

DOI: 10.1172/JCI89885

Maintenance N-acetyl cysteine treatment for bipolar disorder: A double-blind randomized placebo controlled trial

Publisher: Springer Science and Business Media LLC

Date: 14-08-2012

DOI: 10.1186/1741-7015-10-91

Rapid Generation of Dityrosine Cross-linked Aβ Oligomers via Cu-Redox Cycling

Publisher: Humana Press

Date: 2012

DOI: 10.1007/978-1-61779-551-0_1

Abstract: There is a great interest in the role of free radicals and oxidative stress in Alzheimer's disease and for the role of transition metals in the generation of oligomers of Aβ peptides. In the literature, there are a multitude of varying methods that can be used to create soluble oligomers of Aβ, however, the processes that create these oligomers are often stochastic by nature and thus reproducibility is an issue. Here we report a simple and reproducible method for the production of radically derived dityrosine cross-linked oligomers of Aβ, through reaction with copper and ascorbic acid.

Glutathione peroxidase 4: a new player in neurodegeneration?

Publisher: Springer Science and Business Media LLC

Date: 25-10-2016

DOI: 10.1038/MP.2016.196

Abstract: Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme reported as an inhibitor of ferroptosis, a recently discovered non-apoptotic form of cell death. This pathway was initially described in cancer cells and has since been identified in hippoc al and renal cells. In this Perspective, we propose that inhibition of ferroptosis by GPx4 provides protective mechanisms against neurodegeneration. In addition, we suggest that selenium deficiency enhances susceptibility to ferroptotic processes, as well as other programmed cell death pathways due to a reduction in GPx4 activity. We review recent studies of GPx4 with an emphasis on neuronal protection, and discuss the relevance of selenium levels on its enzymatic activity.

Investigation of Brain Iron in Niemann-Pick Type C: A 7T Quantitative Susceptibility Mapping Study

Publisher: American Society of Neuroradiology (ASNR)

Date: 22-06-2023

DOI: 10.3174/AJNR.A7894

β-amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin

Publisher: Public Library of Science (PLoS)

Date: 02-12-2014

DOI: 10.1371/JOURNAL.PONE.0114174

Is early-life iron exposure critical in neurodegeneration?

Publisher: Springer Science and Business Media LLC

Date: 23-06-2015

DOI: 10.1038/NRNEUROL.2015.100

Abstract: The effects of iron deficiency are well documented, but relatively little is known about the long-term implications of iron overload during development. High levels of redox-active iron in the brain have been associated with neurodegenerative disorders, most notably Parkinson disease, yet a gradual increase in brain iron seems to be a feature of normal ageing. Increased brain iron levels might result from intake of infant formula that is excessively fortified with iron, thereby altering the trajectory of brain iron uptake and lifying the risk of iron-associated neurodegeneration in later life. In this Perspectives article, we discuss the potential long-term implications of excessive iron intake in early life, propose the analysis of iron deposits in teeth as a method for retrospective determination of iron exposure during critical developmental windows, and call for evidence-based optimization of the chemical composition of infant dietary supplements.

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

Publisher: Wiley

Date: 19-11-2018

DOI: 10.1111/JNC.14580

Oral Treatment with CuII(atsm) Increases Mutant SOD1 In Vivo but Protects Motor Neurons and Improves the Phenotype of a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Publisher: Society for Neuroscience

Date: 04-06-2014

DOI: 10.1523/JNEUROSCI.4196-13.2014

Nanoscale Imaging Reveals Big Role for Iron in Alzheimer's Disease

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1016/J.CHEMBIOL.2017.10.002

Abstract: In this issue of Cell Chemical Biology, Telling et al. (2017) apply advanced X-ray microscopy techniques to reveal magnetite iron species in plaques from a mouse model of Alzheimer's disease. The characterization of abnormal iron chemistry in the disease model highlights the potential for iron to combine with the β-amyloid peptide and accelerate the disease process.

Unblinded by the light: amyloid‐related imaging abnormalities in Alzheimer’s clinical trials

Publisher: Wiley

Date: 09-09-2020

DOI: 10.1111/ENE.14484

Erratum: φXANES: In vivo imaging of metal-protein coordination environments

Publisher: Springer Science and Business Media LLC

Date: 21-03-2016

DOI: 10.1038/SREP22684

Abstract: Scientific Reports 6: Article number: 20350 published online: 10 February 2016 updated: 21 March 2016 In this Article, the online methods were omitted. The online methods should read: Strains Wild type C. elegans (strain N2) were obtained from the Caenorhabditis Genetics Center (University of Minnesota), and ftn-2(ok404) and the ferritin null ftn-2(ok404) ftn-1(ok3625) (strain GMC005) have been previously described 1 .

S4-02-06 Copper and zinc in Alzheimer's disease: from bench to clinic

Publisher: Elsevier BV

Date: 07-2004

DOI: 10.1016/S0197-4580(04)80236-7

Development of Novel Therapeutics Targeting the Blood–Brain Barrier: From Barrier to Carrier

Publisher: Wiley

Date: 03-06-2021

DOI: 10.1002/ADVS.202101090

Abstract: The blood–brain barrier (BBB) is a highly specialized neurovascular unit, initially described as an intact barrier to prevent toxins, pathogens, and potentially harmful substances from entering the brain. An intact BBB is also critical for the maintenance of normal neuronal function. In cerebral vascular diseases and neurological disorders, the BBB can be disrupted, contributing to disease progression. While restoration of BBB integrity serves as a robust biomarker of better clinical outcomes, the restrictive nature of the intact BBB presents a major hurdle for delivery of therapeutics into the brain. Recent studies show that the BBB is actively engaged in crosstalk between neuronal and the circulatory systems, which defines another important role of the BBB: as an interfacing conduit that mediates communication between two sides of the BBB. This role has been subject to extensive investigation for brain‐targeted drug delivery and shows promising results. The dual roles of the BBB make it a unique target for drug development. Here, recent developments and novel strategies to target the BBB for therapeutic purposes are reviewed, from both barrier and carrier perspectives.

Iron overload and impaired iron handling contribute to the dystrophic pathology in models of Duchenne muscular dystrophy

Publisher: Wiley

Date: 06-03-2022

DOI: 10.1002/JCSM.12950

Abstract: Oxidative stress is implicated in the pathophysiology of Duchenne muscular dystrophy (DMD, caused by mutations in the dystrophin gene), which is the most common and severe of the muscular dystrophies. To our knowledge, the distribution of iron, an important modulator of oxidative stress, has not been assessed in DMD. We tested the hypotheses that iron accumulation occurs in mouse models of DMD and that modulation of iron through the diet or chelation could modify disease severity. We assessed iron distribution and total elemental iron using LA‐ICP‐MS on skeletal muscle cross‐sections of 8‐week‐old Bl10 control mice and dystrophic mdx mice (with moderate dystrophy) and dystrophin/utrophin‐null mice ( dko , with severe dystrophy). In addition, mdx mice (4 weeks) were treated with either an iron chelator (deferiprone 150 mg/kg/day) or iron‐enriched feed (containing 1% added iron as carbonyl iron). Immunoblotting was used to determine the abundance of iron‐ and mitochondria‐related proteins. (Immuno)histochemical and mRNA assessments of fibrosis and inflammation were also performed. We observed a significant increase in total elemental iron in hindlimb muscles of dko mice (+50%, P 0.05) and in the diaphragm of mdx mice (+80%, P 0.05), with both tissues exhibiting severe pathology. Iron dyshomeostasis was further evidenced by an increase in the storage protein ferritin ( dko : +39%, P 0.05) and ferroportin compared with Bl10 control mice ( mdx : +152% and dko : +175%, P 0.05). Despite having features of iron overload, dystrophic muscles had lower protein expression of ALAS‐1, the rate‐limiting enzyme for haem synthesis ( dko −44%, P 0.05), and the haem‐containing protein myoglobin ( dko −54%, P 0.05). Deferiprone treatment tended to decrease muscle iron levels in mdx mice (−30%, P 0.1), which was associated with lower oxidative stress and fibrosis, but suppressed haem‐containing proteins and mitochondrial content. Increasing iron via dietary intervention elevated total muscle iron (+25%, P 0.05) but did not aggravate the pathology. Muscles from dystrophic mice have increased iron levels and dysregulated iron‐related proteins that are associated with dystrophic pathology. Muscle iron levels were manipulated by iron chelation and iron enriched feed. Iron chelation reduced fibrosis and reactive oxygen species (ROS) but also suppressed haem‐containing proteins and mitochondrial activity. Conversely, iron supplementation increased ferritin and haem‐containing proteins but did not alter ROS, fibrosis, or mitochondrial activity. Further studies are required to investigate the contribution of impaired ferritin breakdown in the dysregulation of iron homeostasis in DMD.

The acute phase protein lactoferrin is a key feature of Alzheimer’s disease and predictor of Aβ burden through induction of APP amyloidogenic processing

Publisher: Springer Science and Business Media LLC

Date: 16-08-2021

DOI: 10.1038/S41380-021-01248-1

Abstract: Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia erted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aβ production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aβ production, neuroinflammation and iron dysregulation.

A study protocol for a phase II randomised, double-blind, placebo-controlled trial of sodium selenate as a disease-modifying treatment for behavioural variant frontotemporal dementia

Publisher: BMJ

Date: 11-2020

DOI: 10.1136/BMJOPEN-2020-040100

Abstract: Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder often neuropathologically associated with the accumulation of abnormally hyperphosphorylated tau, for which there is currently no disease-modifying treatment. Previous work by our group has shown sodium selenate upregulates the activity of protein phosphatase 2 in the brain, increasing the rate of tau dephosphorylation. The objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying treatment for bvFTD. This will be a multisite, phase IIb, double-blind placebo-controlled trial of sodium selenate. One hundred and twenty participants will be enrolled across 4 Australian academic hospitals. Following screening eligible participants will be randomised (1:1) to sodium selenate (15 mg three times a day) or placebo for 52 weeks. Participants will have regular safety and efficacy visits throughout the study period. The primary study outcome will be percentage brain volume change (PBVC) as measured on MRI over 52 weeks of treatment. This will be analysed with a general linear model (analysis of covariance (ANCOVA)) with the PBVC as an output, the treatment as an input and the baseline brain volume as covariate for adjustment purposes. Secondary outcomes include safety and tolerability measures, and efficacy measures change in cerebrospinal fluid total-tau, Addenbrooke’s Cognitive Examination-III and Cambridge Behavioural Inventory-Revised scores over the 52 weeks of treatment. These will also be analysed with ANCOVA where the corresponding baseline measure will be incorporated in the model. Additional exploratory outcomes will include other imaging, cognitive and biospecimen analyses. The study was approved by the Human Research and Ethics Committee of the lead site as part of the Australian Multisite Ethics approval system. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. ACTRN12620000236998 .

Monomerized Cu,Zn-superoxide dismutase induces oxidative stress through aberrant Cu binding

Publisher: Elsevier BV

Date: 04-2010

DOI: 10.1016/J.FREERADBIOMED.2010.01.008

Abstract: Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS). Lowering intracellular Cu improves the FALS-like phenotype of mutant SOD1 mice. Using immobilized Cu-affinity chromatography, we have previously shown that mutant SOD1 is expressed as two affinity fractions, one with high affinity for Cu (SOD1(HAC)) and one with low affinity (SOD1(LAC)), whereas wild-type SOD1 is expressed only as SOD1(LAC). Here we further characterize SOD1(HAC) to ascertain the toxicity of mutant SOD1 species. We found that SOD1(HAC) was modified at cysteine residues (Cys) and could be generated from wild-type SOD1 by oxidation of Cys. SOD1(HAC) mainly consisted of monomer, whereas SOD1(LAC) was a dimer. Mutant SOD1s possessed ectopic thiol oxidase activity that was exaggerated by loading it with adventitial Cu, but this activity was minimal in wild-type SOD1. Wild-type SOD1 could be induced to develop the activity by oxidation of Cys. Conversely, mutant SOD1 decreased the activity by being forced away from its monomeric state with a cross-linker. A significant decrease in free thiol concentration was observed in Neuro2a cells transfected with mutant SOD1s when they were treated with Cu. SOD1(HAC) may be pathogenic in FALS by being a monomeric species that gains a redox activity by aberrantly coordinating Cu(2+).

The Neuroinflammatory Acute Phase Response in Parkinsonian‐Related Disorders

Publisher: Wiley

Date: 08-02-2022

DOI: 10.1002/MDS.28958

Abstract: Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings. The aim was to measure a panel of neuroinflammatory acute phase response (APR) proteins in the cerebrospinal fluid (CSF) of participants with PD and related disorders. Eleven APR proteins were measured in the CSF of 867 participants from the BioFINDER cohort who were healthy (612) or had a diagnosis of PD (155), multiple system atrophy (MSA) (26), progressive supranuclear palsy (PSP) (22), dementia with Lewy bodies (DLB) (23), or Parkinson's disease with dementia (PDD) (29). CSF APR proteins were mostly unchanged in PD, with only haptoglobin and α1‐antitrypsin significantly elevated compared to controls. These proteins were variably increased in the other disorders. Certain protein components yielded unique signatures according to diagnosis: ferritin and transthyretin were selectively elevated in MSA and discriminated these patients from all others. Haptoglobin was selectively increased in PSP, discriminating this disease from MSA when used in combination with ferritin and transthyretin. This panel of proteins did not correlate well with severity of motor impairment in any disease category, but several (particularly ceruloplasmin and ferritin) were associated with memory performance (Mini‐Mental State Examination) in patients with DLB and PDD. These findings provide new insights into inflammatory changes in PD and related disorders while also introducing biomarkers of potential clinical diagnostic utility. © 2022 International Parkinson and Movement Disorder Society

Elevated labile Cu is associated with oxidative pathology in Alzheimer disease

Publisher: Elsevier BV

Date: 2012

DOI: 10.1016/J.FREERADBIOMED.2011.10.446

Abstract: Oxidative stress is implicated in Alzheimer disease (AD) pathogenesis, for which evidence indicates that radical species are generated by the redox-active biometal Cu. The contribution of labile Cu to the oxidative stress observed in AD has not been evaluated. The Cu content of postmortem cortical tissue from nondemented elderly controls and AD cases was measured using inductively coupled plasma mass spectroscopy, and the proportion of labile Cu was assessed using the Cu-phenanthroline assay. Further, the capacity of the tissue to stabilize Cu(2+) was evaluated using immobilized metal-affinity chromatography, and the level of tissue oxidative damage was determined by the presence of thiobarbituric acid-reactive compounds. We identified elevated levels of exchangeable Cu(2+), which were correlated with tissue oxidative damage additionally, we noted an increased capacity of AD cortical tissue s les to bind Cu(2+). This deranged Cu homeostasis reflects the homeostatic breakdown of Cu observed in AD and supports biometal metabolism as a therapeutic target.

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Publisher: Springer Science and Business Media LLC

Date: 11-08-2015

DOI: 10.1007/S13311-015-0378-2

Molecular Mechanisms of Glutaredoxin Enzymes: Versatile Hubs for Thiol–Disulfide Exchange between Protein Thiols and Glutathione

Publisher: Elsevier BV

Date: 2019

DOI: 10.1016/J.JMB.2018.12.006

Abstract: The tripeptide glutathione (GSH) and its oxidized form glutathione disulfide (GSSG) constitute a key redox couple in cells. In particular, they partner protein thiols in reversible thiol-disulfide exchange reactions that act as switches in cell signaling and redox homeostasis. Disruption of these processes may impair cellular redox signal transduction and induce redox misbalances that are linked directly to aging processes and to a range of pathological conditions including cancer, cardiovascular diseases and neurological disorders. Glutaredoxins are a class of GSH-dependent oxidoreductase enzymes that specifically catalyze reversible thiol-disulfide exchange reactions between protein thiols and the abundant thiol pool GSSG/GSH. They protect protein thiols from irreversible oxidation, regulate their activities under a variety of cellular conditions and are key players in cell signaling and redox homeostasis. On the other hand, they may also function as metal-binding proteins with a possible role in the cellular homeostasis and metabolism of essential metals copper and iron. However, the molecular basis and underlying mechanisms of glutaredoxin action remain elusive in many situations. This review focuses specifically on these aspects in the context of recent developments that illuminate some of these uncertainties.

Redox-active metals, oxidative stress, and Alzheimer's disease pathology

Publisher: Wiley

Date: 03-2004

DOI: 10.1196/ANNALS.1306.012

Abstract: Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Abeta peptide, the principal component of beta-amyloid that is one of the primary lesions in AD. The binding of metals to Abeta modulates several physiochemical properties of Abeta that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial Abeta amyloid. Studies have confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II) and, to a lesser extent, Fe(III) are reduced in the presence of Abeta with concomitant production of reactive oxygen species (ROS), hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH*). These Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H(2)O(2) mediates Abeta cellular toxicity and increases the production of both Abeta and amyloid precursor protein (APP). Third, the 5' untranslated region (5'UTR) of APP mRNA has a functional iron-response element (IRE), which is consistent with biochemical evidence that APP is a redox-active metalloprotein. Hence, the redox interactions between Abeta, APP, and metals may be at the heart of a pathological positive feedback system wherein Abeta amyloidosis and oxidative stress promote each other. The emergence of redox-active metals as key players in AD pathogenesis strongly argues that amyloid-specific metal-complexing agents and antioxidants be investigated as possible disease-modifying agents for treating this horrible disease.

Iron and Ferroptosis as Therapeutic Targets in Alzheimer’s Disease

Publisher: Springer Science and Business Media LLC

Date: 27-10-2020

DOI: 10.1007/S13311-020-00954-Y

Towards stage specific treatments: Effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia

Publisher: Elsevier BV

Date: 03-2015

DOI: 10.1016/J.PNPBP.2014.10.002

Abstract: Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder all targets of N-acetyl cysteine (NAC). A double blind, placebo controlled trial suggested NAC to be beneficial to those diagnosed with schizophrenia. The current manuscript aims to investigate duration of the illness as a key factor that may be modulating the response to NAC in the participants who took part in the study. A s le of 121 participants were randomised in a double fashion to 24 weeks (placebo=62 NAC=59). Clinical and functional variables were collected over the treatment period. Duration of the illness at baseline was grouped into <10 years, 10- 20 years. Mixed Model Repeated Measures Analysis was used to explore the effect of illness duration on response to treatment with NAC. A significant interaction between duration of the illness and response to treatment with NAC was consistently found for positive symptoms and functional variables, but not for negative or general symptoms or for side effect related outcomes. The pattern of changes suggests that this mediator effect of duration of illness in response to treatment is more evident in those participants with 20 years or more of illness duration. Our results suggest a potential advantage of adjunctive NAC over placebo on functioning and positive symptoms reduction in those patients with chronic schizophrenia. This has potential for suggesting stage specific treatments.

Plasma high-density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume.

Publisher: Wiley

Date: 24-08-2022

DOI: 10.1111/JNC.15681

Abstract: Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippoc al volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data.

Metallothioneins in brain - The role in physiology and pathology

Publisher: Elsevier BV

Date: 02-1997

DOI: 10.1006/TAAP.1996.8054

Abstract: A symposium on the role of brain metallothioneins (MTs) in physiology and pathology was held at the 1996 Annual Society of Toxicology Meeting in Anaheim, California. The objectives of this symposium were to: (1) review the physiologic function of MTs, (2) examine the distribution of brain MTs with particular emphasis on cell-specific localization (neurons vs neuroglia), (3) discuss MT gene responsiveness upon toxic insult with metals, and (4) discuss the potential role of MTs in the etiology of neurodegenerative disorders. Dr. Cherian discussed the biochemical properties of the MTs, emphasizing structural similarities and differences between the MTs. Dr. Klaassen addressed the expression and distribution of the MTs in brains with special reference to the cell-specific localization of MTs. Dr. Aschner provided data illustrating a potential role for MTs in attenuating the cytotoxicity caused by methylmercury (MeHg) in cultured neonatal astrocytes. Dr. Palmiter discussed the properties of MT-III and the increased sensitivity of MT-III knockout mice to kainate-induced seizures. Cerebral zinc metabolism, its relationship to MT homeostasis, and its pathogenic potential in Alzheimer's disease was addressed by Dr. Bush.

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

Publisher: Wiley

Date: 25-01-2021

DOI: 10.1002/ALZ.12282

Abstract: This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large‐scale emerging evidence. Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele ( APOE ) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti‐ferroptotic/iron compound in AD patients. Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well‐established consequence of aging and inflammation, which are major theories of disease pathogenesis.

Human Basic Fibroblast Growth Factor Inhibits Tau Phosphorylation via the PI3K/Akt-GSK3β Signaling Pathway in a 6-Hydroxydopamine-Induced Model of Parkinson's Disease

Publisher: S. Karger AG

Date: 2016

DOI: 10.1159/000445871

Abstract: b i Background: /i /b Basic fibroblast growth factor (bFGF) has been increasingly investigated due to its neuroprotection in neurodegenerative disorders. Because there are still no cures for any of these disorders, it is crucial to identify new therapeutic targets and screen potential drugs. The increased phosphorylation of tau at Ser sup /sup leads to intracellular tau accumulation, which forms neurofibrillary tangles in Parkinson's disease (PD). In this study, neuroprotection by bFGF was observed, and the mechanisms related to its regulation of phosphorylated tau were investigated. b i Methods: /i /b bFGF-loaded liposome carriers were intranasally administered to rats. The neuroprotective effects of bFGF were assessed in a PD model induced by 6-hydroxydopamine (6-OHDA) in vivo and in vitro. The phosphorylation of tau was measured, and the PI3K/Akt-GSK3β signaling pathway was investigated. b i Results: /i /b Our study demonstrated that liposomes markedly assisted in the delivery of bFGF to the striatum and substantia nigra of rats and enhanced the neuroprotective effects of bFGF on dopaminergic neurons. bFGF treatment significantly ameliorated the behavioral deficits induced by 6-OHDA, rescued the loss of tyrosine hydroxylase-positive neurons and increased the number of Nissl bodies. bFGF reduced the phosphorylation of tau and GSK3β and increased the phosphorylation of PI3K/Akt. b i Conclusion: /i /b Liposomes markedly assisted in the delivery of bFGF to the brain and enhanced the neuroprotective effects of bFGF by inhibiting the phosphorylation of tau. bFGF down-regulated the phosphorylation of tau by increasing the phosphorylation of GSK3β via the PI3K/Akt signaling pathway. These findings provide a new vision of bFGF as a potential therapy for PD.

Discussion

Publisher: Elsevier BV

Date: 05-1999

DOI: 10.1016/S0197-4580(99)00058-5

The Clinical Implications of Impaired Zinc Signaling in the Brain

Publisher: Springer Japan

Date: 2014

DOI: 10.1007/978-4-431-55114-0_9

BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer's disease

Publisher: Elsevier BV

Date: 11-2013

DOI: 10.1016/J.NEUROBIOLAGING.2013.05.006

Abstract: Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has previously been implicated in Alzheimer's disease (AD)-related cognitive impairment. We aimed to determine the relationship between BDNF Val66Met and beta-amyloid (Aβ) on cognitive decline, hippoc al atrophy, and Aβ accumulation over 36 months in 165 healthy adults enrolled in the Australian Imaging, Biomarkers and Lifestyle study. In healthy adults with high Aβ, Met carriers showed significant and moderate-to-large declines in episodic memory, executive function, and language, and greater hippoc al atrophy over 36 months, compared with Val/Val homozygotes. BDNF Val66Met was not found to be related to rates of change in cognition or hippoc al volume in healthy adults with low Aβ. BDNF Val66Met did not relate to the amount of Aβ or to the rate of Aβ accumulation in either group. High Aβ levels coupled with Met carriage may be useful prognostic markers of accelerated cognitive decline and hippoc al degeneration in in iduals in the preclinical stage of AD.

The neurobiology of zinc in health and disease

Publisher: Springer Science and Business Media LLC

Date: 13-05-2005

DOI: 10.1038/NRN1671

Abstract: The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for ex le, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for ex le, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'.

N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder-A Double-Blind Randomized Placebo-Controlled Trial

Publisher: Elsevier BV

Date: 09-2008

DOI: 10.1016/J.BIOPSYCH.2008.04.022

Abstract: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorder are complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder. A randomized, double-blind, multicenter, placebo-controlled study of in iduals (n = 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning. NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: -8.05 [-13.16, -2.95], p = .002) and most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p = .968) and no significant between-group differences in adverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts. NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar disorder.

N-acetylcysteine for major depressive episodes in bipolar disorder,N-acetilcisteína para o tratamento de episódios de depressão maior no transtorno bipolar

Publisher: EDITORA SCIENTIFIC

Date: 12-2011

DOI: 10.1590/S1516-44462011000400011

Abstract: OBJECTIVE: In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder. METHOD: Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in in iduals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period. RESULTS: Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint the same was true for only one of the seven participants allocated to placebo. DISCUSSION: These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.

Context matters: Communicating the need for biomarkers for mental illnesses to the general public

Publisher: SAGE Publications

Date: 10-2016

DOI: 10.1177/1039856216654396

Novel in vivo experimental viability assays with high sensitivity and throughput capacity using a bdelloid rotifer

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1016/J.ECOENV.2017.06.005

Abstract: Rotifers have been used in biological research as well-characterized models of aging. Their multi-organ characters and their sensitivity for chemicals and environmental changes make them useful as in vivo toxicological and lifespan models. Our aim was to create a bdelloid rotifer model to use in high-throughput viability and non-invasive assays. In order to identify our species Philodina acuticornis odiosa (PA), 18S rDNA-based phylogenetic analysis was carried out and their species-specific morphological markers identified. To execute the rotifer-based experiments, we developed an oil-covered water-drop methodology adapted from human in vitro fertilization techniques. This enables toxicological observations of in idual one-housed rotifers in a closed and controllable micro-environment for up to several weeks. Hydrogen peroxide (H

Mitochondria in Aging and Alzheimer's Disease

Publisher: Mary Ann Liebert Inc

Date: 09-2007

DOI: 10.1089/REJ.2007.0592

Abstract: Two significant risk factors are inextricably linked with Alzheimer's disease: advancing age, and accumulation of the amyloid-beta peptide. Over the age of 65 the risk of developing Alzheimer's disease increases almost exponentially with age, and the amyloid-beta rich neuritic plaques of the Alzheimer's disease brain are a histopathological hallmark of the disease. Since its identification as a major constituent of neuritic plaques amyloid-beta has attracted intense research focus as the primary causative agent in the development of Alzheimer's disease. As a result, numerous reports now exist to propose potential neurotoxic mechanisms mediated by amyloid-beta. Despite these research efforts, there is still a scarcity of information on the biologic link between aging and amyloid-beta in Alzheimer's disease, and although increasing evidence indicates that intracellular amyloid-beta is acutely toxic, there is also a paucity of information on the mechanisms of neurotoxicity mediated by intracellular amyloid-beta. Functional decline of mitochondria with aging is well established, and growing evidence attributes this decline to loss of mitochondrial DNA integrity in postmitotic cells including neurons. Oxidative stress due to mitochondrial failure may drive increased amyloidogenic processing of the amyloid-beta precursor protein, contributing to a loss of amyloid-beta precursor protein functionality and increased amyloid-beta production. Importantly, recent data show that amyloid-beta accumulates within mitochondria of the Alzheimer's disease brain. We speculate that age-related somatic mutation of mitochondrial DNA may be an important factor underlying sporadic Alzheimer's disease.

Altered levels of blood proteins in Alzheimer's disease longitudinal study: Results from Australian Imaging Biomarkers Lifestyle Study of Ageing cohort

Publisher: Wiley

Date: 2017

DOI: 10.1016/J.DADM.2017.04.003

Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying β-amyloid pathology

Publisher: Elsevier BV

Date: 04-2018

DOI: 10.1016/J.NBD.2018.12.010

Abstract: β-Amyloid pathology is elevated in ~30% of cognitively normal people over 65, and is associated with accelerated neurodegeneration in the pre-clinical stages of Alzheimer's disease. Recent findings reveal that brain iron might also act to propel neurodegeneration in people with underlying amyloid pathology. Here, repeated PET scans of fluorodeoxyglucose (FDG) were used as a biomarker for brain hypometabolism and a downstream biomarker of neurodegeneration to investigate whether levels of ferritin in the cerebrospinal fluid (CSF a reporter of brain iron load) are associated with prodromal disease progression of people with high β-amyloid pathology determined by established cut-off values in CSF t-tau/Aβ

Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson's disease

Publisher: Elsevier BV

Date: 03-2003

DOI: 10.1016/S0896-6273(03)00126-0

Abstract: Studies on postmortem brains from Parkinson's patients reveal elevated iron in the substantia nigra (SN). Selective cell death in this brain region is associated with oxidative stress, which may be exacerbated by the presence of excess iron. Whether iron plays a causative role in cell death, however, is controversial. Here, we explore the effects of iron chelation via either transgenic expression of the iron binding protein ferritin or oral administration of the bioavailable metal chelator clioquinol (CQ) on susceptibility to the Parkinson's-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP). Reduction in reactive iron by either genetic or pharmacological means was found to be well tolerated in animals in our studies and to result in protection against the toxin, suggesting that iron chelation may be an effective therapy for prevention and treatment of the disease.

Serum copper - A biomarker for Alzheimer disease?

Publisher: American Medical Association (AMA)

Date: 05-2004

DOI: 10.1001/ARCHNEUR.61.5.631

Quantitative elemental bio-imaging of Mn, Fe, Cu and Zn in 6-hydroxydopamine induced Parkinsonism mouse models

Publisher: Oxford University Press (OUP)

Date: 2009

DOI: 10.1039/B816188G

Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer's disease

Publisher: Public Library of Science (PLoS)

Date: 11-03-2011

DOI: 10.1371/JOURNAL.PONE.0017669

In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 26-10-2022

DOI: 10.1038/S41537-022-00293-1

Abstract: Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T 1 imaging in 12 in iduals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

Effects of N-acetylcysteine on substance use in bipolar disorder: A randomised placebo-controlled clinical trial

Publisher: Cambridge University Press (CUP)

Date: 12-2009

DOI: 10.1111/J.1601-5215.2009.00397.X

Abstract: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU). Participants were randomised to a 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using a Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU. Among the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumed caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared to placebo at week 2 of treatment but not at other study visits. NAC appeared to have little effect on the participants who were using substances. A larger study on a substance-using population will be necessary to determine if NAC may be a useful treatment for substance use.

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Publisher: Elsevier BV

Date: 03-2016

DOI: 10.1074/JBC.M115.655183

Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum

Publisher: Wiley

Date: 2022

DOI: 10.1002/DAD2.12307

Abstract: We evaluated a new Simoa plasma assay for phosphorylated tau (P‐tau) at aa217 enhanced by additional p‐tau sites (p217+tau). Plasma p217+tau levels were compared to 18 F‐NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18 F‐MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Compared to Aβ− CU, the plasma levels of p217+tau increased 2‐fold in Aβ+ CU and 3.5‐fold in Aβ+ CI. In Aβ− the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64 CU, P = .45) and tau SUVR MT P = .63 (CI, P = .69 CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ− CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ− PET was 0.89, and for tau+ versus tau− PET was 0.89. Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.

Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5'untranslated region

Publisher: Bentham Science Publishers Ltd.

Date: 04-2005

DOI: 10.2174/1567205053585855

Abstract: A pilot study was conducted employing a well known mouse model for Alzheimer's disease to evaluate the anti-amyloid efficacy of three FDA pre-approved drugs. Paroxetine (SSRI and APP 5'UTR directed lead compound), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic) were provided to the drinking water of TgCRND8 mice for three months. This report provides data that measured the steady-state levels of amyloid Abeta-40 and Abeta-42 Abeta as pmol Abeta per gram of mouse brain cortex in drug treated and placebo animals. The relative levels of Abeta peptide levels were reduced after exposure of mice to paroxetine (N=5), NAC (N=7), and erythromycin (N=7) relative to matched placebo counterparts. These results demonstrated proof-of concept for a strategy to further screen the APP 5'UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. These data also demonstrated a statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed.

Disruption of Hfe leads to skeletal muscle iron loading and reduction of hemoproteins involved in oxidative metabolism in a mouse model of hereditary hemochromatosis

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.BBAGEN.2021.130082

Perturbed Iron Biology in the Prefrontal Cortex of People with Schizophrenia

Publisher: Research Square Platform LLC

Date: 18-11-2022

DOI: 10.21203/RS.3.RS-2241794/V1

Abstract: Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n=85), among schizophrenia cases (n=86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in in iduals with the disorder. Such iron-ferritin uncoupling would lead to more free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

Mice overexpressing hepcidin suggest ferroportin does not play a major role in Mn homeostasis

Publisher: Oxford University Press (OUP)

Date: 13-03-2019

DOI: 10.1039/C8MT00370J

Abstract: Manganese is an essential metal that is required for a wide range of biological functions. Ferroportin (FPN), the only known cellular exporter of iron, has also been proposed to play a role in manganese export, but this relationship is incompletely understood. To investigate this in more detail in vivo, we examined the relative distributions of manganese and iron in TMPRSS6 deficient mice, which are characterized by constitutively high expression of the iron regulatory hormone hepcidin and, consequently, very low FPN levels in their tissues. Tmprss6−/− mice showed frank iron deficiency and reduced iron levels in most tissues, consistent with FPN playing an important role in the distribution of this metal, but manganese levels were largely unaffected. Associated studies using intestine-specific FPN knockout mice showed that loss of FPN significantly reduced the dietary absorption of iron, but had no effect on manganese intake. Taken together, our data suggest that FPN does not play a major role in Mn transport in vivo. They do not exclude a minor role for FPN in manganese homeostasis, nor the possibility that the transporter may be relevant at high Mn levels, but at physiological levels of this metal, other transport proteins appear to be more important.

The Efficacy of AdjunctiveN-Acetylcysteine in Major Depressive Disorder

Publisher: Physicians Postgraduate Press, Inc

Date: 15-06-2014

DOI: 10.4088/JCP.13M08454

SLC30A3 Responds to Glucose- and Zinc Variations in ß-Cells and Is Critical for Insulin Production and In Vivo Glucose-Metabolism During ß-Cell Stress

Publisher: Public Library of Science (PLoS)

Date: 25-05-2009

DOI: 10.1371/JOURNAL.PONE.0005684

Effects of Neonatal Iron Feeding and Chronic Clioquinol Administration on the Parkinsonian Human A53T Transgenic Mouse

Publisher: American Chemical Society (ACS)

Date: 07-01-2016

DOI: 10.1021/ACSCHEMNEURO.5B00305

Abstract: Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using clioquinol later in life.

Cu(ATSM) Increases P-Glycoprotein Expression and Function at the Blood-Brain Barrier in C57BL6/J Mice

Publisher: MDPI AG

Date: 03-08-2023

DOI: 10.3390/PHARMACEUTICS15082084

Abstract: P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aβ), a contributor to Alzheimer’s disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aβ levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs. Isolated mBECs treated with Cu(ATSM) (100 nM for 24 h) exhibited a 1.6-fold increase in P-gp expression and a 20% reduction in accumulation of the P-gp substrate rhodamine 123. Oral administration of Cu(ATSM) (30 mg/kg/day) for 28 days led to a 1.5 & 1.3-fold increase in brain microvascular and hepatic expression of P-gp, respectively, and a 20% reduction in BBB transport of [3H]-digoxin. A metallomic analysis showed a 3.5 and 19.9-fold increase in Cu levels in brain microvessels and livers of Cu(ATSM)-treated mice. Our findings demonstrate that Cu(ATSM) increases P-gp expression and function at the BBB in vivo, with implications for CNS drug delivery and clearance of Aβ in AD.

A domain level interaction network of amyloid precursor protein and Aβ of Alzheimer's disease

Publisher: Wiley

Date: 06-2010

DOI: 10.1002/PMIC.200900773

Abstract: The primary constituent of the amyloid plaque, beta-amyloid (Abeta), is thought to be the causal "toxic moiety" of Alzheimer's disease. However, despite much work focused on both Abeta and its parent protein, amyloid precursor protein (APP), the functional roles of APP and its cleavage products remain to be fully elucidated. Protein-protein interaction networks can provide insight into protein function, however, high-throughput data often report false positives and are in frequent disagreement with low-throughput experiments. Moreover, the complexity of the CNS is likely to be under represented in such databases. Therefore, we curated the published work characterizing both APP and Abeta to create a protein interaction network of APP and its proteolytic cleavage products, with annotation, where possible, to the level of APP binding domain and isoform. This is the first time that an interactome has been refined to domain level, essential for the interpretation of APP due to the presence of multiple isoforms and processed fragments. Gene ontology and network analysis were used to identify potentially novel functional relationships among interacting proteins.

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease

Publisher: Springer Science and Business Media LLC

Date: 10-11-2020

DOI: 10.1038/S41467-020-19473-7

Abstract: Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral s les of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including ether lipids, sphingolipids (notably GM 3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.

Correction to: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease (Acta Neuropathologica Communications, (2017), 5, 1, (53), 10.1186/s40478-017-0456-2)

Publisher: Springer Science and Business Media LLC

Date: 29-09-2021

DOI: 10.1186/S40478-021-01258-8

An Iron-responsive Element Type II in the 5′-Untranslated Region of the Alzheimer's Amyloid Precursor Protein Transcript

Publisher: Elsevier BV

Date: 11-2002

DOI: 10.1074/JBC.M207435200

Role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice

Publisher: Bentham Science Publishers Ltd.

Date: 08-2009

DOI: 10.2174/092986709788803060

Abstract: The tripeptide, glutathione (gamma-glutamylcysteinylglycine) is the primary endogenous free radical scavenger in the human body. When glutathione (GSH) levels are reduced there is an increased potential for cellular oxidative stress, characterised by an increase and accruement of reactive oxygen species (ROS). Oxidative stress has been implicated in the pathology of schizophrenia and bipolar disorder. This could partly be caused by alterations in dopaminergic and glutamatergic activity that are implicated in these illnesses. Glutamate and dopamine are highly redox reactive molecules and produce ROS during normal neurotransmission. Alterations to these neurotransmitter pathways may therefore increase the oxidative burden in the brain. Furthermore, mitochondrial dysfunction, as a source of oxidative stress, has been documented in both schizophrenia and bipolar disorder. The combination of altered neurotransmission and this mitochondrial dysfunction leading to oxidative damage may ultimately contribute to illness symptoms. Animal models have been established to investigate the involvement of glutathione depletion in aspects of schizophrenia and bipolar disorder to further characterise the role of oxidative stress in psychopathology. Stemming from preclinical evidence, clinical studies have recently shown antioxidant precursor treatment to be effective in schizophrenia and bipolar disorder, providing a novel clinical angle to augment often suboptimal conventional treatments.

Direct in vivo imaging of essential bioinorganics in Caenorhabditis elegans

Publisher: Oxford University Press (OUP)

Date: 2013

DOI: 10.1039/C3MT00010A

Abstract: Metals are essential in biochemistry, with highly regulated localisation and concentration. To continue elucidating the impact of inorganic physiology on cellular process in health and disease requires development of suitable eukaryotic models and experimental approaches. The multicellular organism Caenorhabditis elegans has been widely adopted as a model system and proved to be highly valuable in biomedical research, and here we record the distribution of physiologically important 4th row elements throughout anesthetised, hydrated adult C. elegans without the need for chemical fixation or mechanical sectioning. Probing the partitioning of elements between intact anatomical structures at subcellular length scales allowed the impact of preparation techniques commonly in use for analytical microanalysis to be assessed. In addition, taking advantage of C. elegans as a research tool, these studies were carried out across a cohort of genetically homogenous in iduals with specific expression of green fluorescent protein within intestinal cells. These studies allowed direct visualisation of elemental co-localisation with anatomical structures and facilitated analysis of inter-animal variability in biometal abundance and localisation. These data reflect stochastic metabolic activity and confirm C. elegans as a sensitive system in which to explore the effects of altered metal homeostasis.

Decreased Copper in Alzheimer’s Disease Brain Is Predominantly in the Soluble Extractable Fraction

Publisher: Hindawi Limited

Date: 2013

DOI: 10.1155/2013/623241

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia and represents a significant burden on the global economy and society. The role of transition metals, in particular copper (Cu), in AD has become of significant interest due to the dyshomeostasis of these essential elements, which can impart profound effects on cell viability and neuronal function. We tested the hypothesis that there is a systemic perturbation in Cu compartmentalization in AD, within the brain as well as in the periphery, specifically within erythrocytes. Our results showed that the previously reported decrease in Cu within the human frontal cortex was confined to the soluble ( P 0.05 ) and total homogenate ( P 0.05 ) fractions. No differences were observed in Cu concentration in erythrocytes. Our data indicate that there is a brain specific alteration in Cu levels in AD localized to the soluble extracted material, which is not reflected in erythrocytes. Further studies using metalloproteomics approaches will be able to elucidate the metabolic mechanism(s) that results in the decreased brain Cu levels during the progression of AD.

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1016/J.CELL.2017.09.021

φXANES: In vivo imaging of metal-protein coordination environments

Publisher: Springer Science and Business Media LLC

Date: 10-02-2016

DOI: 10.1038/SREP20350

Abstract: We have developed an X-ray absorption near edge structure spectroscopy method using fluorescence detection for visualizing in vivo coordination environments of metals in biological specimens. This approach, which we term fluorescence imaging XANES (φXANES), allows us to spatially depict metal-protein associations in a native, hydrated state whilst avoiding intrinsic chemical damage from radiation. This method was validated using iron-challenged Caenorhabditis elegans to observe marked alterations in redox environment.

Increased risk of cognitive impairment in patients with diabetes is associated with metformin

Publisher: American Diabetes Association

Date: 14-09-2013

DOI: 10.2337/DC13-0229

Abstract: To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes. Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n = 480) or mild cognitive impairment (n = 187) and those who were cognitively intact (n = 687) were included patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n = 104) or impaired glucose tolerance (n = 22). Participants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228 adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]). Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

Publisher: Wiley

Date: 05-1999

DOI: 10.1046/J.1471-4159.1999.0722092.X

Abstract: Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-1-nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-beta (Abeta) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Abeta25-35 in the presence or absence of Cu or Fe. Abeta25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Abeta to perturb neuronal GSH homeostasis. Abeta25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.

The plasma membrane redox system in Alzheimer's disease

Publisher: Elsevier BV

Date: 03-2011

DOI: 10.1016/J.EXPNEUROL.2010.12.009

P1-131 (Aβ) in human lens & aqueous humor: further characterization of a novel AD biomarker

Publisher: Elsevier BV

Date: 07-2004

DOI: 10.1016/S0197-4580(04)80454-8

The Complex Role of Apolipoprotein E in Alzheimer’s Disease: an Overview and Update

Publisher: Springer Science and Business Media LLC

Date: 19-09-2016

DOI: 10.1007/S12031-016-0839-Z

Abstract: Apolipoprotein E (ApoE) plays a crucial role in the homeostatic control of lipids in both the periphery and the central nervous system (CNS). In humans, ApoE exists in three different isoforms: ε2, ε3 and ε4. ApoE ε3 is the most common isoform, while the ε4 isoform confers the greatest genetic risk for Alzheimer's disease (AD). However, the mechanisms underlying how ApoE contributes to the pathogenesis of AD are still debated. ApoE has been shown to impact amyloid β (Aβ) deposition and clearance in the brain. ApoE also has Aβ-independent pathways in AD, which has led to the discovery of new roles of ApoE ranging from mitochondria dysfunction to, most recently, iron metabolism. Here, we review the role of ApoE in health and in AD, with the view of identifying therapeutic approaches that could prevent the risk associated with the ε4 isoform.

Increased affinity for copper mediated by cysteine 111 in forms of mutant superoxide dismutase 1 linked to amyotrophic lateral sclerosis

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1016/J.FREERADBIOMED.2007.02.004

Abstract: Mutations in Cu,Zn-superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (ALS). It has been proposed that neuronal cell death might occur due to inappropriately increased Cu interaction with mutant SOD1. Using Cu immobilized metal-affinity chromatography (IMAC), we showed that mutant SOD1 (A4V, G85R, and G93A) expressed in transfected COS7 cells, transgenic mouse spinal cord tissue, and transformed yeast possessed higher affinity for Cu than wild-type SOD1. Serine substitution for cysteine at the Cys111 residue in mutant SOD1 abolished the Cu interaction on IMAC. C111S substitution reversed the accelerated degradation of mutant SOD1 in transfected cells, suggesting that the Cys111 residue is critical for the stability of mutant SOD1. Aberrant Cu binding at the Cys111 residue may be a significant factor in altering mutant SOD1 behavior and may explain the benefit of controlling Cu access to mutant SOD1 in models of familial ALS.

Imaging metals in brain tissue by laser ablation - Inductively coupled plasma - Mass spectrometry (LA-ICP-MS)

Publisher: MyJove Corporation

Date: 22-01-2017

DOI: 10.3791/55042

Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: Implications for Alzheimer β-amyloid pathology

Publisher: Elsevier BV

Date: 05-2006

DOI: 10.1016/J.JINORGBIO.2006.02.010

Abstract: The incidence of Alzheimer's disease (AD) is greater in women than men at any age, as is the development of amyloid pathology in several transgenic mouse models of AD. Due to the involvement of metals in AD pathogenesis, variations between the sexes in metal metabolism may contribute to the sex difference in AD risk. In this study, we investigated sex differences in brain metal levels across the lifespan in mice of two different background strains, as well as in mice overexpressing the human amyloid precursor protein (APP) and amyloid-beta protein (Abeta). We demonstrate consistently lower Cu and higher Mn levels in females compared with males at any age studied. The sex differences in Cu and Mn levels are independent of APP/Abeta expression. AD brain exhibits decreased Cu and increased Mn levels, as do transgenic mice overexpressing APP or Abeta. The age-dependent elevations of Cu, Fe and Co levels were found to be significantly greater in mice of B6/SJL background compared with B6/DBA. If depleting Cu and/or rising Mn levels contribute to AD pathogenesis, natural sex differences in these brain metal levels may contribute to the increased propensity of females to develop AD.

N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia-A Double-Blind, Randomized, Placebo-Controlled Trial

Publisher: Elsevier BV

Date: 09-2008

DOI: 10.1016/J.BIOPSYCH.2008.03.004

Abstract: Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period. A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized 84 completed treatment. Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [-5.97 (-10.44, -1.51), p = .009], PANSS negative [mean difference -1.83 (95% confidence interval: -3.33, -.32), p = .018], and PANSS general [-2.79 (-5.38, -.20), p = .035], CGI-Severity (CGI-S) [-.26 (-.44, -.08), p = .004], and CGI-Improvement (CGI-I) [-.22 (-.41, -.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits. These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.

Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder

Publisher: Elsevier BV

Date: 04-2012

DOI: 10.1016/J.PNPBP.2011.11.011

Abstract: Bipolar disorder (BD) is intricately associated with chronic clinical conditions. Medical comorbidity is not only more prevalent in mood disorders, but is associated with increased costs, cognitive impairment and, ultimately, premature mortality. Oxidative stress and inflammation may mediate part of this association. To further investigate the association between medical comorbidity status and clinical improvement with adjuvant N acetyl cysteine (NAC) in the context of a placebo-controlled trial. Placebo-controlled randomized clinical trial assessing the effect of NAC over 24 weeks. Symptomatic and functional outcomes were collected over the study period. Medical comorbidities were self-reported, and we took special interest in cardiovascular and endocrine conditions. We evaluated change from baseline to endpoint and the interaction between change and reported medical comorbidities. Fifty-one percent of patients reported have a cardiovascular or endocrine comorbidity. Although not found for depressive symptoms or quality of life, a significant interaction between medical comorbidity and change scores was consistently found for all functional outcomes. This indicated an advantage of NAC over placebo in those with a clinical comorbidity. Systemic illness moderated only the effect of NAC on functioning, not on depression. Demonstrating an improvement in functional outcomes with an agent that modulates redox and inflammatory pathways, this study lends empirical support to the idea that medical and psychiatric comorbidity are additive in contributing to allostatic states. One intriguing possibility is that comorbid clinical illness could be a marker for more severe oxidative stress states--and thus guide antioxidant use--in BD.

Regional iron distribution and soluble ferroprotein profiles in the healthy human brain

Publisher: Elsevier BV

Date: 03-2020

DOI: 10.1016/J.PNEUROBIO.2019.101744

Abstract: Iron is essential for brain development and health where its redox properties are used for a number of neurological processes. However, iron is also a major driver of oxidative stress if not properly controlled. Brain iron distribution is highly compartmentalised and regulated by a number of proteins and small biomolecules. Here, we examine heterogeneity in regional iron levels in 10 anatomical structures from seven post-mortem human brains with no apparent neuropathology. Putamen contained the highest levels, and most case-to-case variability, of iron compared with the other regions examined. Partitioning of iron between cytosolic and membrane-bound iron was generally consistent in each region, with a slightly higher proportion (55 %) in the 'insoluble' phase. We expand on this using the Allen Human Brain Atlas to examine patterns between iron levels and transcriptomic expression of iron regulatory proteins and using quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry to assess regional differences in the molecular masses to which cytosolic iron predominantly binds. Approximately 60 % was associated with ferritin, equating to approximately 25 % of total tissue iron essentially in storage. This study is the first of its kind in human brain tissue, providing a valuable resource and new insight for iron biologists and neuroscientists, alike.

A delicate balance: Iron metabolism and diseases of the brain

Publisher: Frontiers Media SA

Date: 2013

DOI: 10.3389/FNAGI.2013.00034

Cerebrospinal fluid ceruloplasmin levels predict cognitive decline and brain atrophy in people with underlying β-amyloid pathology

Publisher: Elsevier BV

Date: 06-2020

DOI: 10.1016/J.NBD.2020.104810

Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 09-03-2016

DOI: 10.1038/NPJSCHZ.2016.2

Abstract: Our expression microarray studies showed messenger RNA (mRNA) for solute carrier family 39 (zinc transporter), member 12 ( SLC39A12 ) was higher in dorsolateral prefrontal cortex from subjects with schizophrenia (Sz) in comparison with controls. To better understand the significance of these data we ascertained whether SLC39A12 mRNA was altered in a number of cortical regions (Brodmann’s area (BA) 8, 9, 44) from subjects with Sz, in BA 9 from subjects with mood disorders and in rats treated with antipsychotic drugs. In addition, we determined whether inducing the expression of SLC39A12 resulted in an increased cellular zinc uptake. SLC39A12 variant 1 and 2 mRNA was measured using quantitative PCR. Zinc uptake was measured in CHO cells transfected with human SLC39A12 variant 1 and 2. In Sz, compared with controls, SLC39A12 variant 1 and 2 mRNA was higher in all cortical regions studied. The were no differences in levels of mRNA for either variant of SLC39A12 in BA 9 from subjects with mood disorders and levels of mRNA for Slc39a1 2 was not different in the cortex of rats treated with antipsychotic drugs. Finally, expressing both variants in CHO-K1 cells was associated with an increase in radioactive zinc uptake. As increased levels of murine Slc39a12 mRNA has been shown to correlate with increasing cellular zinc uptake, our data would be consistent with the possibility of a dysregulated zinc homeostasis in the cortex of subjects with schizophrenia due to altered expression of SLC39A12 .

A novel approach to rapidly prevent age-related cognitive decline

Publisher: Wiley

Date: 04-12-2014

DOI: 10.1111/ACEL.12178

Cognitive effects of adjunctive N-acetyl cysteine in psychosis

Publisher: Cambridge University Press (CUP)

Date: 29-11-2016

DOI: 10.1017/S0033291716002932

Abstract: Cognitive deficits are predictors of functional outcome in patients with psychosis. While conventional antipsychotics are relatively effective on positive symptoms, their impact on negative and cognitive symptoms is limited. Recent studies have established a link between oxidative stress and neurocognitive deficits in psychosis. N -acetylcysteine (NAC), a glutathione precursor with glutamatergic properties, has shown efficacy on negative symptoms and functioning in patients with schizophrenia and bipolar disorder, respectively. However, there are few evidence-based approaches for managing cognitive impairment in psychosis. The present study aims to examine the cognitive effects of adjunctive NAC treatment in a pooled subgroup of participants with psychosis who completed neuropsychological assessment in two trials of both schizophrenia and bipolar disorder. A s le of 58 participants were randomized in a double fashion to receive 2 g/day of NAC ( n = 27) or placebo ( n = 31) for 24 weeks. Attention, working memory and executive function domains were assessed. Differences between cognitive performance at baseline and end point were examined using Wilcoxon's test. The Mann–Whitney test was used to examine the differences between the NAC and placebo groups at the end point. Participants treated with NAC had significantly higher working memory performance at week 24 compared with placebo ( U = 98.5, p = 0.027). NAC may have an impact on cognitive performance in psychosis, as a significant improvement in working memory was observed in the NAC-treated group compared with placebo however, these preliminary data require replication. Glutamatergic compounds such as NAC may constitute a step towards the development of useful therapies for cognitive impairment in psychosis.

How iron can drive neurodegeneration

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.TINS.2023.02.003

Selenium, selenoproteins and neurodegenerative diseases

Publisher: Oxford University Press (OUP)

Date: 13-05-2015

DOI: 10.1039/C5MT00075K

Abstract: It is unsurprising that our understanding of the role of selenium in neurological function is somewhat immature, considering its relatively recent discovery as an essential element to human health. Selenocysteine, the 21st amino acid, is the defining feature of the 25 selenoprotein-encoding genes so far discovered within the human genome. The low abundance of these proteins in the brain belies the integral role they play in normal neurological function, from well-characterised antioxidant activity in the periphery to poorly understood mechanisms that modulate mitochondrial function and response to brain pathology. Selenium has been identified as playing a role in several neurodegenerative disorders, including Alzheimer's and Parkinson's disease, though its function as a ‘cause or effect’ of disease process remains unclear. This review discusses selenium metabolism in detail, specifically with regard to the role it plays within the central nervous system, and examines the most current literature investigating how selenium may be involved in chronic diseases of the central nervous system.

Motor and cognitive deficits in aged tau knockout mice in two background strains

Publisher: Springer Science and Business Media LLC

Date: 14-08-2014

DOI: 10.1186/1750-1326-9-29

Chelation and intercalation: Complementary properties in a compound for the treatment of Alzheimer's disease

Publisher: Elsevier BV

Date: 06-2000

DOI: 10.1006/JSBI.2000.4285

Blood-Based Protein Biomarkers for Diagnosis of Alzheimer Disease

Publisher: American Medical Association (AMA)

Date: 10-2012

DOI: 10.1001/ARCHNEUROL.2012.1282

Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease

Publisher: Springer Science and Business Media LLC

Date: 10-07-2014

DOI: 10.1186/1750-1326-9-27

Ceruloplasmin and β-amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron

Publisher: Elsevier BV

Date: 04-2014

DOI: 10.1016/J.FREERADBIOMED.2014.01.041

Abstract: Traumatic brain injury (TBI) is in part complicated by pro-oxidant iron elevation independent of brain hemorrhage. Ceruloplasmin (CP) and β-amyloid protein precursor (APP) are known neuroprotective proteins that reduce oxidative damage through iron regulation. We surveyed iron, CP, and APP in brain tissue from control and TBI-affected patients who were stratified according to time of death following injury. We observed CP and APP induction after TBI accompanying iron accumulation. Elevated APP and CP expression was also observed in a mouse model of focal cortical contusion injury concomitant with iron elevation. To determine if changes in APP or CP were neuroprotective we employed the same TBI model on APP(-/-) and CP(-/-) mice and found that both exhibited exaggerated infarct volume and iron accumulation postinjury. Evidence supports a regulatory role of both proteins in defence against iron-induced oxidative damage after TBI, which presents as a tractable therapeutic target.

Zinc in the physiology and pathology of the CNS

Publisher: Springer Science and Business Media LLC

Date: 14-10-2009

DOI: 10.1038/NRN2734

Abstract: The past few years have witnessed dramatic progress on all frontiers of zinc neurobiology. The recent development of powerful tools, including zinc-sensitive fluorescent probes, selective chelators and genetically modified animal models, has brought a deeper understanding of the roles of this cation as a crucial intra- and intercellular signalling ion of the CNS, and hence of the neurophysiological importance of zinc-dependent pathways and the injurious effects of zinc dyshomeostasis. The development of some innovative therapeutic strategies is aimed at controlling and preventing the damaging effects of this cation in neurological conditions such as stroke and Alzheimer's disease.

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease

Publisher: Springer Science and Business Media LLC

Date: 02-2021

DOI: 10.1038/S41467-021-21057-Y

Abstract: Aging and Alzheimer’s disease (AD) are associated with progressive brain disorganization. Although structural asymmetry is an organizing feature of the cerebral cortex it is unknown whether continuous age- and AD-related cortical degradation alters cortical asymmetry. Here, in multiple longitudinal adult lifespan cohorts we show that higher-order cortical regions exhibiting pronounced asymmetry at age ~20 also show progressive asymmetry-loss across the adult lifespan. Hence, accelerated thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This organizational principle showed high consistency across cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating s les. Asymmetry-change was further accelerated in AD. Results suggest a system-wide dedifferentiation of the adaptive asymmetric organization of heteromodal cortex in aging and AD.

Metal ions and Alzheimer's disease

Publisher: Springer US

Date: 2007

DOI: 10.1007/978-0-387-70830-0_15

Plasma apolipoprotein e and Alzheimer disease risk: The AIBL study of aging

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 21-03-2011

DOI: 10.1212/WNL.0B013E318211C352

Translating the Rosetta Stone of N-Acetylcysteine

Publisher: Elsevier BV

Date: 06-2012

DOI: 10.1016/J.BIOPSYCH.2012.04.001

Three-month stability of the cogstate brief battery in healthy older adults, mild cognitive impairment, and alzheimer's disease: Results from the Australian imaging, biomarkers, and lifestyle-rate of change substudy (AIBL-ROCS)

Publisher: Oxford University Press (OUP)

Date: 03-04-2013

DOI: 10.1093/ARCLIN/ACT021

Abstract: Large prospective studies of Alzheimer's disease (AD) have sought to understand the pathological evolution of AD and factors that may influence the rate of disease progression. Estimates of rates of cognitive change are available for 12 or 24 months, but not for shorter time frames (e.g., 3 or 6 months). Most clinical drug trials seeking to reduce or modify AD symptoms have been conducted over 12- or 24-week periods. As such, we aimed to characterize the performance of a group of healthy older adults, adults with amnestic mild cognitive impairment (aMCI), and adults with AD on the CogState battery of tests over short test-retest intervals. This study recruited 105 healthy older adults, 48 adults with aMCI, and 42 adults with AD from the Australian Imaging, Biomarkers, and Lifestyle study and administered the CogState battery monthly over 3 months. The CogState battery of tests showed high test-retest reliability and stability in all clinical groups when participants were assessed over 3 months. When considered at baseline, the CogState battery of tests was able to detect AD-related cognitive impairment. The data provide important estimates of the reliability, stability, and variability of each cognitive test in healthy older adults, adults with aMCI, and adults with AD. This may potentially be used to inform future estimates of cognitive change in clinical trials.

Alzheimer disease β-amyloid activity mimics cholesterol oxidase

Publisher: American Society for Clinical Investigation

Date: 09-2005

DOI: 10.1172/JCI23610

Tat-haFGF 14–154 Upregulates ADAM10 to Attenuate the Alzheimer Phenotype of APP/PS1 Mice through the PI3K-CREB-IRE1α/XBP1 Pathway

Publisher: Elsevier BV

Date: 06-2017

DOI: 10.1016/J.OMTN.2017.05.004

Amyloidogenic processing of Alzheimer’s disease β-amyloid precursor protein induces cellular iron retention

Publisher: Springer Science and Business Media LLC

Date: 22-05-2020

DOI: 10.1038/S41380-020-0762-0

Iron chelation by deferiprone does not rescue the Niemann-Pick Disease Type C1 mouse model

Publisher: Springer Science and Business Media LLC

Date: 25-02-2020

DOI: 10.1007/S10534-020-00233-5

Copper Promotes the Trafficking of the Amyloid Precursor Protein

Publisher: Elsevier BV

Date: 03-2011

DOI: 10.1074/JBC.M110.128512

The PESERA coarse scale erosion model for Europe. I. - Model rationale and implementation

Publisher: Wiley

Date: 19-11-2008

DOI: 10.1111/J.1365-2389.2008.01072.X

Oxidative processes in Alzheimer's disease: the role of Aβ-metal interactions

Publisher: Elsevier BV

Date: 07-2000

DOI: 10.1016/S0531-5565(00)00112-1

Abstract: Alzheimer's disease is characterized by signs of a major oxidative stress in the neocortex and the concomitant deposition of Amyloid beta (Abeta). Abeta is a metalloprotein that binds copper, and is electrochemically active. Abeta converts molecular oxygen into hydrogen peroxide by reducing copper or iron, and this may lead to Fenton chemistry. Hydrogen peroxide is a freely permeable prooxidant that may be responsible for many of the oxidative adducts that form in the Alzheimer-affected brain. The electrochemical activity of various Abeta species correlates with the peptides' neurotoxicity in cell culture, and participation in the neuropathology of Alzheimer's disease. These reactions present a novel target for Alzheimer therapeutics.

Elevated cortical zinc in Alzheimer disease

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-07-2006

DOI: 10.1212/01.WNL.0000223644.08653.B5

Abstract: To determine whether changes in brain biometals in Alzheimer disease (AD) and in normal brain tissue are tandemly associated with amyloid beta-peptide (Abeta) burden and dementia severity. The authors measured zinc, copper, iron, manganese, and aluminum and Abeta levels in postmortem neocortical tissue from patients with AD (n = 10), normal age-matched control subjects (n = 14), patients with schizophrenia (n = 26), and patients with schizophrenia with amyloid (n = 8). Severity of cognitive impairment was assessed with the Clinical Dementia Rating Scale (CDR). There was a significant, more than twofold, increase of tissue zinc in the AD-affected cortex compared with the other groups. Zinc levels increased with tissue amyloid levels. Zinc levels were significantly elevated in the most severely demented cases (CDR 4 to 5) and in cases that had an amyloid burden greater than 8 plaques/mm(2). Levels of other metals did not differ between groups. Brain zinc accumulation is a prominent feature of advanced Alzheimer disease (AD) and is biochemically linked to brain amyloid beta-peptide accumulation and dementia severity in AD.

mRNA Treatment Rescues Niemann–Pick Disease Type C1 in Patient Fibroblasts

Publisher: American Chemical Society (ACS)

Date: 20-09-2022

DOI: 10.1021/ACS.MOLPHARMACEUT.2C00463

Abstract: Messenger RNA (mRNA) holds great potential as a disease-modifying treatment for a wide array of monogenic disorders. Niemann-Pick disease type C1 (NP-C1) is an ultrarare monogenic disease that arises due to loss-of-function mutations in the

Sequestration of Copper from β-Amyloid Promotes Selective Lysis by Cyclen-Hybrid Cleavage Agents

Publisher: Elsevier BV

Date: 11-2008

DOI: 10.1074/JBC.M804722200

Oxidation of Iron under Physiologically Relevant Conditions in Biological Fluids from Healthy and Alzheimer's Disease Subjects

Publisher: American Chemical Society (ACS)

Date: 03-01-2017

DOI: 10.1021/ACSCHEMNEURO.6B00411

Abstract: Ferroxidase activity has been reported to be altered in various biological fluids in neurodegenerative disease, but the sources contributing to the altered activity are uncertain. Here we assay fractions of serum and cerebrospinal fluid with a newly validated triplex ferroxidase assay. Our data indicate that while ceruloplasmin, a multicopper ferroxidase, is the predominant source of serum activity, activity in CSF predominantly derives from a <10 kDa component, specifically from polyanions such as citrate and phosphate. We confirm that in human biological s les, ceruloplasmin activity in serum is decreased in Alzheimer's disease, but in CSF a reduction of activity in Alzheimer's disease originates from the polyanion component.

A blood-based biomarker panel indicates IL-10 and IL-12/23p40 are jointly associated as predictors of β-amyloid load in an AD cohort

Publisher: Springer Science and Business Media LLC

Date: 25-10-2017

DOI: 10.1038/S41598-017-14020-9

Abstract: Alzheimer’s Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose in iduals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify in iduals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer’s participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk in iduals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ε4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ε4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of in iduals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial.

The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene

Publisher: Springer Science and Business Media LLC

Date: 12-1993

DOI: 10.1038/NG1293-344

Abstract: Wilson disease (WD) is an autosomal recessive disorder characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain. As shown in the accompanying paper, linkage disequilibrium & haplotype analysis confirmed the disease locus to a single marker interval at 13q14.3. Here we describe a partial cDNA clone (pWD) which maps to this region and shows a particular 76% amino acid homology to the Menkes disease gene, Mc1. The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease-specific mutations, provide convincing evidence that pWD is the Wilson disease gene.

21st century cognitive behavioural therapy for anger: A systematic review of research design, methodology and outcome

Publisher: Cambridge University Press (CUP)

Date: 21-02-2018

DOI: 10.1017/S1352465818000048

Abstract: Background: Past reviews of cognitive behavioural therapy (CBT) for anger have focused on outcome in specific subpopulations, with few questions posed about research design and methodology. Since the turn of the century, there has been a surge of methodologically varied studies awaiting systematic review. Aims: The basic aim was to review this recent literature in terms of trends and patterns in research design, operationalization of anger, and covariates such as social desirability bias (SDB). Also of interest was clinical outcome. Method: After successive culling, 42 relevant studies were retained. These were subjected to a rapid evidence assessment (REA) with special attention to design (ranked on the Scientific Methods Scale) measurement methodology (self-monitored behaviour, anger questionnaires, and others’ ratings), SDB assessment, and statistical versus clinical significance. Results: The randomized controlled trial characterized 60% of the studies, and the State Trait Anger Expression Inventory was the dominant measure of anger. All but one of the studies reported statistically significant outcome, and all but one of the 21 studies evaluating clinical significance laid claim to it. The one study with neither statistical nor clinical significance was the only one that had assessed and corrected for SDB. Conclusions: Measures remain relatively narrow in scope, but study designs have improved, and the outcomes suggest efficacy and clinical effectiveness. In conjunction with previous findings of an inverse relationship between anger and SDB, the results raise the possibility that the favourable picture of CBT for anger may need closer scrutiny with SDB and other methodological details in mind.

KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE ϵ4-positive cognitively normal adults with high Aβ-amyloid burden

Publisher: Springer Science and Business Media LLC

Date: 02-2018

DOI: 10.1038/S41598-018-20513-Y

Abstract: A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein ( KIBRA ) gene has been associated with cognition and hippoc al volume in cognitively normal (CN) in iduals. However, the impact of rs17070145 on longitudinal cognitive decline and hippoc al atrophy in CN adults at greatest risk of developing Alzheimer’s disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippoc al atrophy over six years in 602 CN adults, with known brain Aβ-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aβ-amyloid levels across study duration. In comparison to APOE ε4-ve in iduals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0 . 006 verbal episodic memory, p = 0 . 004 ), and hippoc al atrophy ( p = 0 . 04 ) were observed in in iduals who were APOE ε4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aβ-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aβ-amyloid and APOE ε4.

Copper status in Alzheimer's disease and other neurodegenerative disorders 2013

Publisher: Hindawi Limited

Date: 2013

DOI: 10.1155/2013/838274

Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE

Publisher: Springer Science and Business Media LLC

Date: 19-05-2015

DOI: 10.1038/NCOMMS7760

Abstract: Brain iron elevation is implicated in Alzheimer’s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer’s risk allele, APOE-ɛ4 . These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.

Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment

Publisher: Elsevier BV

Date: 15-01-2005

DOI: 10.1016/J.FREERADBIOMED.2004.10.023

Abstract: Alzheimer disease is characterized by cerebral Abeta deposition, which we have recently discovered occurs also in the lens as cataracts in Alzheimer disease patients. Here we report the presence of significantly increased cataracts in the lenses of an Abeta-transgenic mouse model for Alzheimer disease and their amelioration upon treatment with EUK-189, a synthetic SOD/catalase mimetic. These data support an oxidative etiology for AD-associated lens cataracts and their potential to be treated preventatively with antioxidants.

Copper and Alzheimer Disease: The Good, the Bad and the Ugly

Publisher: Springer New York

Date: 2012

DOI: 10.1007/978-1-4419-9663-3_30

Copper and lipid metabolism: A reciprocal relationship

Publisher: Elsevier BV

Date: 11-2021

DOI: 10.1016/J.BBAGEN.2021.129979

Copper, Zinc, and the Metallobiology of Alzheimer Disease

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 07-2003

DOI: 10.1097/00002093-200307000-00005

Traumatic brain injury induces elevation of Co in the human brain

Publisher: Oxford University Press (OUP)

Date: 2015

DOI: 10.1039/C4MT00258J

Abstract: Following acute brain injury ( hours post-event), cobalt levels in the brain are significantly elevated. This elevation may have important implications for positron emission tomography neuroimaging for assessing brain injury severity.

Striking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in Alzheimer's Disease

Publisher: Mary Ann Liebert Inc

Date: 07-2023

DOI: 10.1089/ARS.2023.0318

Predicting Alzheimer disease from a blood-based biomarker profile

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 17-08-2016

DOI: 10.1212/WNL.0000000000003094

Abstract: We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying in iduals with high or low neocortical β-amyloid burden (NAB), to determine whether it could also identify in iduals at risk of progression to Alzheimer disease (AD) within 54 months. We generated the blood-based signature for 585 healthy controls (HCs) and 74 participants with mild cognitive impairment (MCI) from the Australian Imaging, Biomarkers and Lifestyle Study who underwent clinical reclassification (blinded to biomarker findings) at 54-month follow-up. The in iduals were split into estimated high and low NAB groups based on a cutoff of 1.5 standardized uptake value ratio. We assessed the predictive accuracy of the high and low NAB groupings based on progression to mild cognitive impairment or AD according to clinical reclassification at 54-month follow-up. Twelve percent of HCs with estimated high NAB progressed in comparison to 5% of HCs with estimated low NAB (odds ratio = 2.4). Forty percent of the participants with MCI who had estimated high NAB progressed in comparison to 5% of the participants with MCI who had estimated low NAB (odds ratio = 12.3). These ratios are in line with those reported for Pittsburgh compound B–PET results. In iduals with estimated high NAB had faster rates of memory decline than those with estimated low NAB. These findings suggest that a simple blood-based signature not only provides estimates of NAB but also predicts cognitive decline and disease progression, identifying in iduals at risk of progressing toward AD at the prodromal and preclinical stages.

Homocysteine potentiates copper‐ and amyloid beta peptide‐mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's‐type neurodegenerative pathways

Publisher: Wiley

Date: 03-2001

DOI: 10.1046/J.1471-4159.2001.00178.X

Abstract: Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. Oxidative damage could result from interactions between highly reactive transition metals such as copper (Cu) and endogenous reducing and/or oxidizing molecules in the brain. One such molecule, homocysteine, a thiol-containing amino acid, has previously been shown to modulate Cu toxicity in HeLa and endothelial cells in vitro. Due to a possible link between hyperhomocysteinemia and AD, we examined whether interaction between homocysteine and Cu could potentiate Cu neurotoxicity. Primary mouse neuronal cultures were treated with homocysteine and either Cu (II), Fe (II or III) or Zn (II). Homocysteine was shown to selectively potentiate toxicity from low micromolar concentrations of Cu. The toxicity of homocysteine/Cu coincubation was dependent on the ability of homocysteine to reduce Cu (II) as reflected by the inhibition of toxicity with the Cu (I)-specific chelator, bathocuproine disulphonate. This was supported by data showing that homocysteine reduced Cu (II) more effectively than cysteine or methionine but did not reduce Fe (III) to Fe (II). Homocysteine also generated high levels of hydrogen peroxide in the presence of Cu (II) and promoted Abeta/Cu-mediated hydrogen peroxide production and neurotoxicity. The potentiation of metal toxicity did not involve excitotoxicity as ionotropic glutamate receptor antagonists had no effect on neurotoxicity. Homocysteine alone also had no effect on neuronal glutathione levels. These studies suggest that increased copper and/or homocysteine levels in the elderly could promote significant oxidant damage to neurons and may represent additional risk factor pathways which conspire to produce AD or related neurodegenerative conditions.

Behavioural phenotype of APPC100.V717F transgenic mice over-expressing a mutant Aβ-bearing fragment is associated with reduced NMDA receptor density

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1016/J.BBR.2010.01.013

Abstract: The aim of this study was to characterize APPC100.V717F transgenic (TgC100.V717F) mice which over-express a mutant C100 fragment of the amyloid precursor protein. The mice were compared to TgC100 wild type mice (TgC100.WT) and non-transgenic controls at 4-9 and 16-22 months of age. TgC100.V717F mice showed behavioural hyperactivity, particularly at a younger age, as shown by increased numbers of elevated plus maze arm entries and Y-maze arm entries, enhanced baseline locomotor activity in the open field, and enhanced hetamine-induced hyperlocomotion. This hyperactivity was less pronounced in TgC100.WT which only displayed significant differences to non-transgenic controls at a younger age for the number of Y-maze arm entries and baseline locomotor activity in the open field. In addition, TgC100.V717F mice, but not TgC100.WT, demonstrated cognitive deficits, as shown by reduced spontaneous alternation in the Y-maze and markedly reduced retention in a passive avoidance test. At an older age, TgC100.V717F mice showed enhanced startle and increased immobility time in the forced swim test. In the TgC100.V717F mice, but not TgC100.WT, the behavioural changes were paralleled by a significant reduction in the expression of hippoc al NMDA receptor subunits types 1 and 2A. Concomitantly, we detected axonal disruption and apoptosis in the hippoc us of TgC100.V717F mice. In conclusion, these data demonstrate that the mutant C100 fragment is an effector of biochemical and both cognitive and non-cognitive behaviours. These transgenic mice may be a model for the psychotic features associated with early Alzheimer's disease.

Direct in vivo imaging of ferrous iron dyshomeostasis in ageing Caenorhabditis elegans

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C5SC00233H

Abstract: Synchrotron-based X-ray fluorescence imaging and metalloproteomics reveals a loss of iron homeostasis in ageing Caenorhabditis elegans .

Follow-up plasma apolipoprotein E levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) cohort

Publisher: Springer Science and Business Media LLC

Date: 20-02-2015

DOI: 10.1186/S13195-015-0105-6

Presenilin Promotes Dietary Copper Uptake

Publisher: Public Library of Science (PLoS)

Date: 07-05-2013

DOI: 10.1371/JOURNAL.PONE.0062811

Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats

Publisher: Elsevier BV

Date: 12-2010

DOI: 10.1016/J.EJPHAR.2010.09.035

Abstract: Glutathione (GSH) is the primary antioxidant in the body and is present in high levels in the brain. Levels of GSH and other antioxidants are significantly altered in major psychiatric illnesses, such as schizophrenia. Recent clinical trials have demonstrated that chronic treatment with N-acetyl-l-cysteine (NAC), a GSH precursor, improved symptoms in in iduals with this illness. We previously showed in rats and mice that depletion of GSH by treatment with 2-cyclohexene-1-one (CHX) induced short-term spatial memory deficits in the Y-maze test. The aim of present study was to characterise the effect of NAC in this CHX-induced glutathione depletion model. Consistent with our previous studies, CHX treatment induced approximately 50% reduction of GSH levels in striatum, hippoc us and frontal cortex tissue. GSH depletion was significantly rescued by either 1.2 g/kg or 1.6 g/kg of NAC administration, with a full recovery observed in the frontal cortex after the high dose of NAC. CHX treatment also induced a disruption in short-term spatial recognition memory in Y-maze test, as measured by the duration of time spent in the novel arm. This disruption was reversed by treatment with 1.6 g/kg of NAC. In conclusion, this study suggests that rescue of depleted levels of GSH in the brain restores cognitive deficits, as measured by the Y-maze. These effects appear to be dose-dependent and region-specific. These results may be relevant to the understanding and management of the cognitive symptoms of schizophrenia and bipolar disorder.

Utility of an improved model of amyloid-beta (Aβ1-42) toxicity in Caenorhabditis elegans for drug screening for Alzheimer’s disease

Publisher: Springer Science and Business Media LLC

Date: 2012

DOI: 10.1186/1750-1326-7-57

Profiling the iron, copper and zinc content in primary neuron and astrocyte cultures by rapid online quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry

Publisher: Oxford University Press (OUP)

Date: 2013

DOI: 10.1039/C3MT00227F

Abstract: Metals often determine the chemical reactivity of the proteins to which they are bound. Each cell in the body tightly maintains a unique metalloproteomic profile, mostly dependent on function. This paper describes an analytical online flow injection quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) method, which was applied to profiling the metal-binding proteins found in primary cultures of neurons and astrocytes. This method can be conducted using similar amounts of s le to those used for Western blotting (20-150 μg protein), and has a turnaround time of <15 minutes. Metalloprotein standards for Fe (as ferritin), Cu and Zn (as superoxide dismutase-1) were used to construct multi-point calibration curves for online quantification of metalloproteins by SEC-ICP-MS. Homogenates of primary neuron and astrocyte cultures were analysed by SEC-ICP-MS. Online quantification by external calibration with metalloprotein standards determined the mass of metal eluting from the column relative to time (as pg s(-1)). Total on-column Fe, Cu and Zn detection limits ranged from 0.825 ± 0.005 ng to 13.6 ± 0.7 pg. Neurons and astrocytes exhibited distinct metalloprotein profiles, featuring both ubiquitous and unique metalloprotein species. Separation and detection by SEC-ICP-MS allows appraisal of these metalloproteins in their native state, and online quantification was achieved using this relatively simple external calibration process.

N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial

Publisher: Elsevier BV

Date: 03-2011

DOI: 10.1016/J.JAD.2010.08.001

Abstract: The evidence base for the pharmacological treatment of bipolar II disorder is limited. In bipolar disorder, there is evidence for glutathione depletion and increased oxidative stress, as well as dysregulation of glutamate N-acetyl cysteine (NAC) has effects on both of these systems. Add-on NAC has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. In this report, we explore the effects of this compound in a subset of patients with bipolar II disorder from that trial. In iduals were randomized to NAC or placebo in addition to treatment as usual, in a double-blind fashion. Mood and functional outcomes were assessed up to 24 weeks of treatment. Fourteen in iduals were available for this report, seven in each group. Six people achieved full remission of both depressive and manic symptoms in the NAC group this was true for only two people in the placebo group (χ(2)=4.67, p=0.031). Subgroup analyses in a small subs le of patients. Not all participants had elevated depression scores at baseline. Notwithstanding all the limitations that subgroup analysis of trials carry, this data could serve as a hypothesis-generating stimulus for further clinical trials of pharmacologic treatment for bipolar II depression.

Metal chelation as a potential therapy for Alzheimer's disease

Publisher: Wiley

Date: 12-2000

DOI: 10.1111/J.1749-6632.2000.TB06938.X

Abstract: Alzheimer's disease is a rapidly worsening public health problem. The current lack of effective treatments for Alzheimer's disease makes it imperative to find new pharmacotherapies. At present, the treatment of symptoms includes use of acetylcholinesterase inhibitors, which enhance acetylcholine levels and improve cognitive functioning. Current reports provide evidence that the pathogenesis of Alzheimer's disease is linked to the characteristic neocortical amyloid-beta deposition, which may be mediated by abnormal metal interaction with A beta as well as metal-mediated oxidative stress. In light of these observations, we have considered the development of drugs that target abnormal metal accumulation and its adverse consequences, as well as prevention or reversal of amyloid-beta plaque formation. This paper reviews recent observations on the possible etiologic role of A beta deposition, its redox activity, and its interaction with transition metals that are enriched in the neocortex. We discuss the effects of metal chelators on these processes, list existing drugs with chelating properties, and explore the promise of this approach as a basis for medicinal chemistry in the development of novel Alzheimer's disease therapeutics.

Axonal dispatch of iron in neuronal signaling

Publisher: Springer Science and Business Media LLC

Date: 18-11-2019

DOI: 10.1038/S41589-019-0394-3

Targeting metals rescues the phenotype in an animal model of tauopathy

Publisher: Oxford University Press (OUP)

Date: 2018

DOI: 10.1039/C8MT00153G

Abstract: Targeting metals improves the behavioural, anatomical and biochemical phenotype present in a mouse model of tauopathy.

An anemia of Alzheimer's disease

Publisher: Springer Science and Business Media LLC

Date: 14-01-2014

DOI: 10.1038/MP.2013.178

Abstract: Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that in iduals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.

Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

Publisher: MDPI AG

Date: 19-06-2019

DOI: 10.3390/PH12020093

Abstract: Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

Zinc-induced Alzheimer‘s Abeta1-40 aggregation is mediated by conformational factors

Publisher: Elsevier BV

Date: 10-1997

DOI: 10.1074/JBC.272.42.26464

Tau suppresses microtubule-regulated pancreatic insulin secretion

Publisher: Springer Science and Business Media LLC

Date: 21-09-2023

DOI: 10.1038/S41380-023-02267-W

Disturbed Copper Bioavailability in Alzheimer's Disease

Publisher: Hindawi Limited

Date: 2011

DOI: 10.4061/2011/345614

Abstract: Recent data from in vitro, animal, and human studies have shed new light on the positive roles of copper in many aspects of AD. Copper promotes the non-amyloidogenic processing of APP and thereby lowers the A β production in cell culture systems, and it increases lifetime and decreases soluble amyloid production in APP transgenic mice. In a clinical trial with Alzheimer patients, the decline of A β levels in CSF, which is a diagnostic marker, is diminished in the verum group (8 mg copper/day), indicating a beneficial effect of the copper treatment. These observations are in line with the benefit of treatment with compounds aimed at normalizing metal levels in the brain, such as PBT2. The data reviewed here demonstrate that there is an apparent disturbance in metal homeostasis in AD. More research is urgently needed to understand how this disturbance can be addressed therapeutically.

Association of metals with the risk and clinical characteristics of Parkinson's disease

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/J.PARKRELDIS.2018.05.022

Abstract: While metals have been implicated in the pathophysiology of Parkinson's disease (PD), the clinical evidence is scarce. Further, the contribution of metals for the risk or clinical presentation of PD remains to be explored. To investigate the associations between the level of metals in blood serum and PD risk or clinical presentation, including sex-related differences, we studied 325 PD patients and age- and sex-matched 304 controls. We collected clinical data of the PD patients, including age at onset, PD duration, levodopa-equivalent dose (LED), Hoehn and Yahr stage (H-Y stage), presence of motor fluctuation, levodopa-induced dyskinesia (LID), freezing of gait, hallucination, and Mini-Mental State Examination (MMSE) score. Iron, copper, and zinc levels in serum were assayed by inductively coupled plasma mass spectrometry. Statistical analyses were performed to determine the sex-related differences in metal levels. Among the three metal elements tested, serum copper levels showed significant correlations with PD risk or clinical presentation. Higher copper levels were associated with a decreased PD risk. Higher copper or lower iron levels were associated with the risk of LID in women. Serum copper levels were negatively correlated with MMSE scores in PD patients. This clinical study suggests significant associations between serum metal levels and PD risk or essential clinical features, demonstrating the possible roles of metals in PD pathogenesis or symptom development.

Zinc and Alzheimer's Disease: An Update

Publisher: Informa UK Limited

Date: 1999

DOI: 10.1080/1028415X.1999.11747277

The βA4 Amyloid Protein Precursor in Human Circulation

Publisher: Wiley

Date: 09-1993

DOI: 10.1111/J.1749-6632.1993.TB23048.X

Abstract: beta A4, the principal constituent of the brain amyloid collections in Alzheimer's disease, is derived from a much larger precursor, the amyloid protein precursor (APP). APP exists in the blood as full-length, potentially amyloidogenic forms in platelets, and as an attenuated species in plasma and T-lymphocytes. Studies of circulating APP facilitate the elaboration of the function of this protein, as well as the elucidation of its processing in health and disease.

Erratum: Alzheimer disease β-amyloid activity mimics cholesterol oxidase (Journal of Clinical Investigation (2000) 115 (2556-2563) DOI:10.1172/JCI23610)

Publisher: American Society for Clinical Investigation

Date: 02-10-2006

DOI: 10.1172/JCI23610C1

Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

Publisher: Elsevier BV

Date: 04-2015

DOI: 10.1016/J.REDOX.2015.02.002

BH3 mimetic drugs cooperate with Temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells

Publisher: Springer Science and Business Media LLC

Date: 24-03-2022

DOI: 10.1038/S41418-022-00977-2

Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha-Synuclein hA53T Transgenic Mice

Publisher: American Chemical Society (ACS)

Date: 30-10-2016

DOI: 10.1021/ACSCHEMNEURO.5B00253

Abstract: The abnormal accumulation of alpha-synuclein (α-syn) has been linked to a number of neurodegenerative disorders, the most noteworthy of which is Parkinson's disease. Alpha-synuclein itself is not toxic and fulfills various physiological roles in the central nervous system. However, specific types of aggregates have been shown to be toxic, and metals have been linked to the assembly of these toxic aggregates. In this paper, we have characterized a transgenic mouse that overexpresses the A53T mutation of human α-syn, specifically assessing cognition, motor performance, and subtle anatomical markers that have all been observed in synucleinopathies in humans. We hypothesized that treatment with the moderate-affinity metal chelator, clioquinol (CQ), would reduce the interaction between metals and α-syn to subsequently improve the phenotype of the A53T animal model. We showed that CQ prevents an iron-synuclein interaction, the formation of urea-soluble α-syn aggregates, α-syn-related substantia nigra pars compacta cell loss, reduction in dendritic spine density of hippoc al and caudate putamen medium spiny neurons, and the decline in motor and cognitive function. In conclusion, our data suggests that CQ is capable of mitigating the pathological metal/α-syn interactions, suggesting that the modulation of metal ions warrants further study as a therapeutic approach for the synucleinopathies.

Metal chaperones prevent zinc-mediated cognitive decline

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1016/J.NBD.2014.12.012

Abstract: Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95 AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippoc us. While we demonstrated a small regional increase in hippoc al zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippoc al formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease.

Role of Metals in Alzheimer Disease

Publisher: Wiley

Date: 09-06-2010

DOI: 10.1002/9780470572702.CH24

Altered selenium status in Huntington's disease: Neuroprotection by selenite in the N171-82Q mouse model

Publisher: Elsevier BV

Date: 11-2014

DOI: 10.1016/J.NBD.2014.06.022

Abstract: Disruption of redox homeostasis is a prominent feature in the pathogenesis of Huntington's disease (HD). Selenium an essential element nutrient that modulates redox pathways and has been reported to provide protection against both acute neurotoxicity (e.g. meth hetamine) and chronic neurodegeneration (e.g. tauopathy) in mice. The objective of our study was to investigate the effect of sodium selenite, an inorganic form of selenium, on behavioral, brain degeneration and biochemical outcomes in the N171-82Q Huntington's disease mouse model. HD mice, which were supplemented with sodium selenite from 6 to 14 weeks of age, demonstrated increased motor endurance, decreased loss of brain weight, decreased mutant huntingtin aggregate burden and decreased brain oxidized glutathione levels. Biochemical studies revealed that selenite treatment reverted HD-associated changes in liver selenium and plasma glutathione in N171-82Q mice and had effects on brain selenoprotein transcript expression. Further, we found decreased brain selenium content in human autopsy brain. Taken together, we demonstrate a decreased selenium phenotype in human and mouse HD and additionally show some protective effects of selenite in N171-82Q HD mice. Modification of selenium metabolism results in beneficial effects in mouse HD and thus may represent a therapeutic strategy.

Presenilins Promote the Cellular Uptake of Copper and Zinc and Maintain Copper Chaperone of SOD1-dependent Copper/Zinc Superoxide Dismutase Activity

Publisher: Elsevier BV

Date: 03-2011

DOI: 10.1074/JBC.M110.163964

Biological metals and Alzheimer's disease: Implications for therapeutics and diagnostics

Publisher: Elsevier BV

Date: 09-2010

DOI: 10.1016/J.PNEUROBIO.2010.04.003

Abstract: The equilibrium of metal ions is critical for many physiological functions, particularly in the central nervous system, where metals are essential for development and maintenance of enzymatic activities, mitochondrial function, myelination, neurotransmission as well as learning and memory. Due to their importance, cells have evolved complex machinery for controlling metal-ion homeostasis. However, disruption of these mechanisms, or absorption of detrimental metals with no known biological function, alter the ionic balance and can result in a disease state, including several neurodegenerative disorders such as Alzheimer's disease. Understanding the complex structural and functional interactions of metal ions with the various intracellular and extracellular components of the central nervous system, under normal conditions and during neurodegeneration, is essential for the development of effective therapies. Accordingly, assisting the balance of metal ions back to homeostatic levels has been proposed as a disease-modifying therapeutic strategy for Alzheimer's disease as well as other neurodegenerative diseases.

Cognitive consequences of high Aβ amyloid in mild cognitive impairment and healthy older adults: Implications for early detection of Alzheimer’s disease.

Publisher: American Psychological Association (APA)

Date: 05-2013

DOI: 10.1037/A0032321

Abstract: It has been proposed that only mild cognitive impairment (MCI) with high Aβ amyloid is indicative of incipient Alzheimer's disease (AD), yet MCI with low Aβ amyloid may reflect other neurodegenerative processes. We aimed to determine the extent to which high Aβ amyloid influenced cognitive function in healthy older adults and adults with MCI. Healthy controls (HC n = 178) and adults with MCI (n = 56) enrolled in the Australian Imaging, Biomarkers, and Lifestyle study, underwent positron emission tomography neuroimaging for Aβ amyloid and completed an extensive neuropsychological battery, assessing the cognitive domains of verbal and visual episodic memory, executive function, visuoconstruction, attention and processing speed, and language at baseline. MCI with low Aβ performed worse than MCI with high Aβ on measures of executive function, attention, visuoconstruction and language. No differences were observed between HC high and low Aβ groups. When compared with HC with low Aβ, both MCI high and low Aβ groups performed worse on measures of episodic memory. However, only the MCI low Aβ group performed worse than HC low Aβ on measures of executive function, attention, visuoconstruction, and language. When compared with HC with low Aβ amyloid, MCI with high Aβ amyloid present with impairments restricted to episodic memory, and the episodic memory impairments in MCI with low Aβ amyloid were accompanied by impairments in executive function, attention, visuoconstruction, and language, suggesting that MCI with high Aβ amyloid reflects prodromal AD, although further longitudinal data is required to confirm this.

An iron–dopamine index predicts risk of parkinsonian neurodegeneration in the substantia nigra pars compacta

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C3SC53461H

Abstract: Imaging of iron and dopamine by laser ablation-inductively coupled plasma-mass spectrometry reveals a risk index for parkinsonian neurodegeneration

Author Correction: Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease

Publisher: Springer Science and Business Media LLC

Date: 07-02-2022

DOI: 10.1038/S41467-022-28514-2

Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Publisher: Springer Science and Business Media LLC

Date: 23-02-2022

DOI: 10.1038/S41392-022-00917-Z

Abstract: Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes roteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.

HYPOTHALAMIC ATRIAL-NATRIURETIC-PEPTIDE SECRETION PLASTICITY - DIFFERENTIAL MODULATION OF ALPHA-ADRENOCEPTOR AND BETA-ADRENOCEPTOR

Publisher: S. Karger AG

Date: 1990

DOI: 10.1159/000125540

Abstract: Increasing evidence suggests that atrial natriuretic peptide (ANP), a 28 amino acid peptide with biologically active 4-28 and 5-28 congeners, modulates salt-water homeostasis at both peripheral and central levels. In rats, immunoreactive (ir) ANP is found in hypothalamic (HT) neurons of preoptic and paraventricular regions rich in aminergic innervation. Employing a well-characterized perifusion model of rat HT explants, the acute effects of norepinephrine (NE) on HT release of irANP were examined. Pulsatile administration (20 min) of NE (10(-7) to 10(-5) M) induced a dose-related release of irANP. The stimulatory effect of 10(-5) M NE (2.66 +/- 0.54 pg/ml/HT, means +/- SE, n = 12) was abolished in the presence of 10(-7) M propranolol, a beta-antagonist, but was 50% higher when administrated with 10(-5) M phentolamine, an alpha-antagonist. Administration of equivalent doses of propranolol or phentolamine alone, consistently suppressed (40% below basal secretion rate, BSR) or stimulated (50% above BSR) irANP release, respectively. In addition, infusion of isoprenaline (10(-5) M), a beta-agonist, enhanced BSR by 45%, whilst phenylephrine (10(-5) M), an alpha-agonist, suppressed it by 25%. We conclude that in rat hypothalami (1) occupancy of the beta-adrenoceptor by its agonist stimulates irANP release, (2) alpha- and beta-adrenoceptors modulate irANP secretion in an opposing manner, and (3) the basal release of irANP is a product of the activation of alpha- and beta-adrenoceptors by their endogenous ligands.

Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron

Publisher: Elsevier BV

Date: 11-2002

DOI: 10.1074/JBC.M204379200

Radioiodinated clioquinol as a biomarker for beta-amyloid: Zn2+ complexes in Alzheimer's disease

Publisher: Wiley

Date: 02-2006

DOI: 10.1111/J.1474-9726.2006.00196.X

Abstract: Neocortical beta-amyloid (Abeta) aggregates in Alzheimer's disease (AD) are enriched in transition metals that mediate assembly. Clioquinol (CQ) targets metal interaction with Abeta and inhibits amyloid pathology in transgenic mice. Here, we investigated the binding properties of radioiodinated CQ ([(125)I]CQ) to different in vitro and in vivo Alzheimer models. We observed saturable binding of [(125)I]CQ to synthetic Abeta precipitated by Zn(2+) (K(d)=0.45 and 1.40 nm for Abeta(1-42) and Abeta(1-40), respectively), which was fully displaced by free Zn(2+), Cu(2+), the chelator DTPA (diethylene triamine pentaacetic acid) and partially by Congo red. Sucrose density gradient of post-mortem AD brain indicated that [(125)I]CQ concentrated in a fraction enriched for both Abeta and Zn, which was modulated by exogenous addition of Zn(2+) or DTPA. APP transgenic (Tg2576) mice injected with [(125)I]CQ exhibited higher brain retention of tracer compared to non-Tg mice. Autoradiography of brain sections of these animals confirmed selective [(125)I]CQ enrichment in the neocortex. Histologically, both thioflavine-S (ThS)-positive and negative structures were labeled by [(125)I]CQ. A pilot SPECT study of [(123)I]CQ showed limited uptake of the tracer into the brain, which did however, appear to be more rapid in AD patients compared to age-matched controls. These data support metallated Abeta species as the neuropharmacological target of CQ and indicate that this drug class may have potential as in vivo imaging agents for Alzheimer neuropathology.

Zinc affects the proteolytic stability of Apolipoprotein E in an isoform-dependent way

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1016/J.NBD.2015.06.016

Abstract: The pathological role of zinc in Alzheimer's disease (AD) is not yet fully elucidated, but there is strong evidence that zinc homeostasis is impaired in the AD brain and that this contributes to disease pathogenesis. In this study we examined the effects of zinc on the proteolysis of synthetic Apolipoprotein E (ApoE), a protein whose allelic variants differentially contribute to the onset rogression of disease. We have demonstrated that zinc promotes the proteolysis (using plasma kallikrein, thrombin and chymotrypsin) of synthetic ApoE in an isoform-specific way (E4>E2 and E3), resulting in more ApoE fragments, particularly for ApoE4. In the absence of exogenous proteases there was no effect of metal modulation on either lipidated or non-lipidated ApoE isoforms. Thus, increased zinc in the complex milieu of the ageing and AD brain could reduce the level of normal full-length ApoE and increase other forms that are involved in neurodegeneration. We further examined human plasma s les from people with different ApoE genotypes. Consistent with previous studies, plasma ApoE levels varied according to different genotypes, with ApoE2 carriers showing the highest total ApoE levels and ApoE4 carriers the lowest. The levels of plasma ApoE were not affected by either the addition of exogenous metals (copper, zinc or iron) or by chelation. Taken together, our study reveals that zinc may contribute to the pathogenesis of AD by affecting the proteolysis of ApoE, which to some extent explains why APOE4 carriers are more susceptible to AD.

Genetically Decreased Spinal Cord Copper Concentration Prolongs Life in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Publisher: Society for Neuroscience

Date: 08-09-2004

DOI: 10.1523/JNEUROSCI.2000-04.2004

Abstract: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS) by gain of an aberrant function that is not yet well understood. The role of Cu 2+ in mediating the toxicity of mutant SOD1 has been earnestly contested. We tested the in vivo effects of genetically induced copper deprivation on the ALS phenotype of transgenic mice expressing G86R mutant mouse SOD1, a protein that fails to incorporate Cu 2+ in its active site. Genetically copper-deficient SOD1 G86R transgenic mice were produced by mating SOD1 G86R males to female carriers of the X-linked mottled/brindled (Mobr) mutation. We found that the Mobr allele causes a severe (∼60%) depletion of spinal cord copper levels however, despite the burden of double genetic lesions, it lengthens the lives of SOD1 G86R transgenic mice by 9%. These findings provide evidence supporting a role for copper in the pathogenesis of FALS linked to SOD1 mutations.

Biological metals and metal-targeting compounds in major neurodegenerative diseases

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C4CS00138A

Abstract: Metals are functionally essential, but redistribute in neurodegenerative disease where they induce protein aggregates, catalyze radical formation, and lose bioavailability.

The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5 '-untranslated region

Publisher: Wiley

Date: 12-2004

DOI: 10.1196/ANNALS.1332.003

Abstract: The Alzheimer's amyloid precursor protein (APP) is the metalloprotein that is cleaved to generate the pathogenic Abeta peptide. We showed that iron closely regulated the expression of APP by 5'-untranslated region (5'-UTR) sequences in APP mRNA. Iron modulated APP holoprotein expression by a pathway similar to iron control of the translation of the ferritin-L and -H mRNAs by iron-responsive elements in their 5'-UTRs. APP gene transcription is also responsive to copper deficit where the Menkes protein depleted fibroblasts of copper to suppress transcription of APP through metal regulatory and copper regulatory sequences upstream of the APP 5' cap site. APP is a copper-zinc metalloprotein and chelation of Fe(3+) by desferrioxamine and Cu(2+) by clioquinol appeared to provide effective therapy for the treatment of AD in limited patient studies. We have introduced an RNA-based screen for small APP 5'-UTR binding molecules to identify leads that limit APP translation (but not APLP-1 and APLP-2) and amyloid Abeta peptide production. A library of 1200 drugs was screened to identify lead drugs that limited APP 5'-UTR-directed translation of a reporter gene. The efficacy of these leads was confirmed for specificity in a cell-based secondary assay to measure the steady-state levels of APP holoprotein relative to APLP-1/APLP-2 by Western blotting. Several chelators were identified among the APP 5'-UTR directed leads consistent with the presence of an IRE stem-loop in front of the start codon of the APP transcript. The APP 5'-UTR-directed drugs--desferrioxamine (Fe(3+) chelator), tetrathiomolybdate (Cu(2+) chelator), and dimercaptopropanol (Pb(2+) and Hg(2+) chelator)--each suppressed APP holoprotein expression (and lowered Abeta peptide secretion). The novel anticholinesterase phenserine also provided "proof of concept" for our strategy to target the APP 5'-UTR sequence to identify "anti-amyloid" drugs. We further defined the interaction between iron chelation and phenserine action to control APP 5'-UTR-directed translation in neuroblastoma (SY5Y) transfectants. Phenserine was most efficient to block translation under conditions of intracellular iron chelation with desferrioxamine suggesting that this anticholinesterase operated through an iron (metal)-dependent pathway at the APP 5'-UTR site.

Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis Enteropathica

Publisher: Public Library of Science (PLoS)

Date: 28-08-2013

DOI: 10.1371/JOURNAL.PONE.0072543

Syntaxin 5 Is Required for Copper Homeostasis in Drosophila and Mammals

Publisher: Public Library of Science (PLoS)

Date: 20-12-2010

DOI: 10.1371/JOURNAL.PONE.0014303

Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy.

Publisher: Springer Science and Business Media LLC

Date: 28-04-2022

DOI: 10.1038/S41380-022-01568-W

Abstract: Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer's disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC

Blood and brain protein levels of ubiquitin-conjugating enzyme E2K (UBE2K) are elevated in individuals with schizophrenia

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1016/J.JPSYCHIRES.2019.03.005

Abstract: A number of recent studies have suggested the ubiquitin proteasome system (UPS) in schizophrenia is dysfunctional. The purpose of this study was to investigate UBE2K, a ubiquitin-conjugating (E2) enzyme within the UPS that has been associated with psychosis symptom severity, in the blood and brain of in iduals with schizophrenia. Whole blood and erythrocytes from 128 (71 treatment-resistant schizophrenia, 57 healthy controls) in iduals as well as frozen dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) post-mortem s les from 74 (37 schizophrenia, 37 controls) in iduals were obtained. UBE2K gene expression was assayed in whole blood and DLPFC s les, whereas protein levels were assayed in erythrocytes and OFC s les. Elevated levels of UBE2K mRNA were observed in whole blood of in iduals with schizophrenia (p = 0.03) but not in the DLPFC, while protein levels were raised in erythrocytes and the OFC (p < 0.001 and p = 0.002 respectively). Findings were not better explained by age, smoking, clozapine plasma levels or duration of illness. Although blood and brain s les were derived from independent s les, our findings suggest peripheral protein levels of UBE2K may serve as a surrogate of brain levels and further supports the notion of UPS dysfunction in schizophrenia. Future studies to determine the pathophysiological effects of elevated UBE2K protein levels in the brain of those with schizophrenia are warranted.

Alzheimer's Disease, β-Amyloid Protein and Zinc

Publisher: Elsevier BV

Date: 05-2000

DOI: 10.1093/JN/130.5.1488S

Systematic review protocol: Quantitative susceptibility mapping of brain iron accumulation in neurodegenerative diseases

Publisher: Cold Spring Harbor Laboratory

Date: 19-02-2020

DOI: 10.1101/2020.02.18.20022608

Abstract: Iron has been found to play an important role in neurodegeneration. Quantitative susceptibility mapping (QSM) is a relatively new – and the most accurate - MRI technique available for assessment of iron deposition in the brain. There is a rapidly growing number of studies using QSM to investigate brain iron distribution in neurodegenerative diseases including but not limited to Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington disease and Wilson’s disease. These studies have shown increased iron deposition in the brain regions that are associated with the pathology of the disease. Additionally, QSM is found to be accurate in differential diagnosis of neurodegenerative diseases where clinical presentations are indistinguishable. Structural changes evidenced by QSM are reported to precede the onset of clinical manifestation of neurodegenerative diseases suggesting its benefit in early diagnosis. To our knowledge, no systematic review of QSM findings in neurodegenerative diseases has been published before. A systematic synthesis and conclusion of the existing evidence can improve our understanding of the pathophysiology of neurodegeneration, describe the clinical and research utility of QSM, and point out the direction for future studies in neuropsychiatric disorders. This document is a systematic review protocol developed in accordance with Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) guideline. This protocol is prepared as a guide for conducting a systematic review of studies investigating brain iron and microstructural changes in neurodegenerative diseases using quantitative susceptibility mapping (QSM). This protocol has also been submitted to Prospective Register of Systematic Reviews (PROSPERO) for registration. By publishing this protocol, we aim to enhance clarity and transparency of our systematic review and minimise the risk of bias in the process of its development.

An integrated mass spectrometry imaging and digital pathology workflow for objective detection of colorectal tumours by unique atomic signatures

Publisher: Royal Society of Chemistry (RSC)

Date: 2021

DOI: 10.1039/D1SC02237G

Abstract: Digital pathology and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging reveals a unique elemental signature of colorectal cancer.

Generation and characterization of human induced pluripotent stem cell lines from a familial Alzheimer's disease PSEN1 A246E patient and a non-demented family member bearing wild-type PSEN1

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.SCR.2018.08.006

Abstract: The induced pluripotent stem cell (iPSC) lines UOWi002-A and UOWi003-A were reprogrammed from dermal fibroblasts via mRNA transfection. Dermal fibroblasts from a 56 year old female caucasian familial Alzheimer's disease patient carrying A246E mutation in the PSEN1 gene (familial AD3, autopsy confirmed Alzheimer's disease) and a 75 year old female non-demented control from the same family bearing the wild-type PSEN1 A246 genotype were obtained from the Coriell Institute (AG06848 and AG06846, respectively). The generated iPSCs were characterized and pluripotency was confirmed. The PSEN1 genotype was maintained in both iPSC lines. Resource table.

Increased risk of cognitive impairment in patients with diabetes is associated with metformin

Publisher: American Diabetes Association

Date: 10-05-2014

DOI: 10.2337/DC14-0278

Parkinson's disease prevalence and the association with rurality and agricultural determinants

Publisher: Elsevier BV

Date: 04-2019

DOI: 10.1016/J.PARKRELDIS.2018.10.026

Abstract: Parkinson's disease prevalence has been associated with rurality and pesticide use in studies throughout the world. Here, Parkinson's disease (PD) medication usage was used to estimate prevalence in 79 urban and rural localities in Victoria, Australia (5.3 million people). An ecological study design was used to determine whether PD medication usage, as a reporter of PD diagnosis, differed between 79 regions in Victoria, and whether variance in PD prevalence was associated with population demographics using multiple regression. Cluster formation probability was calculated using Monte Carlo modelling. The association between agricultural production and PD prevalence was conducted with Bonferroni-adjusted Mann-Whitney-U tests. PD prevalence in Victoria was estimated to be 0.85%, which was greater in rural (1.02%) compared to urban (0.80%) locations a difference that was abolished when corrected for demographic variables. Four of the highest prevalent regions (regardless of covariate adjustment) were clustered in northwest Victoria a formation that was unlikely to be due to chance (P = 0.00095). These regions had increased production of pulse crops. PD prevalence was not associated with rurality, but associated with areas of pulse production. Pulses are plants of the fabaceae family, where many of these species secrete the PD toxin, rotenone, as a natural pesticide, which may underlie increased risk. This study is limited by the data collection method, where people who do not take PD medication for their disease, or take PD-associated medication for other diseases, may impact the estimated prevalence.

Plasma p217+tau vs NAV4694 amyloid and MK6240 tau PET across the Alzheimer continuum

Publisher: Cold Spring Harbor Laboratory

Date: 19-02-2022

DOI: 10.1101/2022.02.16.22271024

Abstract: We evaluated a new Simoa plasma assay for phosphorylated tau at aa217 enhanced by additional ptau sites (p217+tau). Plasma p217+tau levels were compared to 18 F-NAV4694 amyloid-beta (Aβ) PET and 18 F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Compared to Aβ-CU, the plasma levels of p217+tau increased two-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ-the p217+tau levels did not significantly differ between CU, MCI or dementia. P217+tau correlated with Aβ centiloids ρ=0.67 (CI 0.64 CU 0.45) and tau SUVR MT ρ=0.63 (CI 0.69 CU 0.34). Area under curve (AUC) for AD vs Aβ-CU was 0.94, for AD vs other dementia was 0.93, for Aβ+ vs Aβ– PET was 0.89 and for tau+ vs tau-PET was 0.89. Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET. Systematic review: The authors reviewed the literature using PubMed, meeting abstracts and presentations. Plasma phospho-tau measures compare well to PET and post-mortem across the continuum of AD but accuracy varies across ptau target sites and assay methods. There are no reports comparing PET to plasma assays targeting multiple sites of tau phosphorylation as typically found in AD. The p217+tau assay targets p217 with binding enhanced by phosphorylation at additional sites such as aa212. Interpretation: Plasma p217+tau elevates early and correlates with both Aβ and tau as measured by PET indicating that tau phosphorylation is an early event in AD and occurs with Aβ deposition. Plasma p217+tau measurement should assist both selection for trials and diagnosis of AD. Future directions: Further validation studies, head-to-head comparison to other assays, assessing the influence of co-morbidities and the ability to measure change in brain Aβ and tau levels are required.

Parallels between the redox properties and toxicity of A beta in Alzheimer's disease and mutant Cu/Zn-SOD in familial amyotrophic lateral sclerosis

Publisher: Wiley

Date: 28-03-2001

DOI: 10.1002/0470846453.CH36

Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease

Publisher: Wiley

Date: 19-02-2013

DOI: 10.1002/ANA.23817

Abstract: Ceruloplasmin is an iron-export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic Parkinson disease (PD) cases, which could contribute to the pro-oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD.

β-amyloid in biological samples: Not all Aβ detection methods are created equal

Publisher: Frontiers Media SA

Date: 13-08-2014

DOI: 10.3389/FNAGI.2014.00203

Copper and zinc in Alzheimer's disease and amyotrophic lateral sclerosis

Publisher: Cambridge University Press

Date: 02-06-2005

DOI: 10.1017/CBO9780511544873.014

N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2000

DOI: 10.1097/00001756-200008030-00029

Abstract: Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SODI) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAC, an over-the-counter antioxidant, could be explored in clinical trials for ALS.

Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons

Publisher: Frontiers Media SA

Date: 03-12-2014

DOI: 10.3389/FNAGI.2014.00319

Therapeutic targets in the biology of Alzheimerʼs disease

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 07-2001

DOI: 10.1097/00001504-200107000-00018

Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease

Publisher: Wiley

Date: 2020

DOI: 10.1002/DAD2.12005

RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine

Publisher: Bentham Science Publishers Ltd.

Date: 07-2006

DOI: 10.2174/156720506777632835

Redox-active iron mediates amyloid-β toxicity

Publisher: Elsevier BV

Date: 02-2001

DOI: 10.1016/S0891-5849(00)00494-9

Abstract: While amyloid-beta toxicity is mediated by oxidative stress and can be attenuated by antioxidants, the actual biochemical mechanism underlying neurotoxicity remains to be established. However, since aggregated amyloid-beta can interact with transition metals, such as iron, both in vitro and in vivo, we suspected that bound iron might be the mediator of toxicity such that holo- and apo-amyloid would have differential effects on cellular viability. Here we demonstrate that when amyloid-beta is pretreated with the iron chelator deferoxamine, neuronal toxicity is significantly attenuated while conversely, incubation of holo-amyloid-beta with excess free iron restores toxicity to original levels. These data, taken together with the known sequelae of amyloid-beta, suggest that the toxicity of amyloid-beta is mediated, at least in part, via redox-active iron that precipitates lipid peroxidation and cellular oxidative stress.

Mediator effects of parameters of inflammation and neurogenesis from a N-acetyl cysteine clinical-trial for bipolar depression

Publisher: Cambridge University Press (CUP)

Date: 16-07-2018

DOI: 10.1017/NEU.2018.13

Abstract: This study aimed to explore effects of adjunctive treatment with N -acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression. This is a secondary analysis of a placebo-controlled randomised trial. Serum s les were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers. Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters. The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression.

The galvanization of β-amyloid in Alzheimer's disease

Publisher: Proceedings of the National Academy of Sciences

Date: 28-05-2002

DOI: 10.1073/PNAS.122249699

Physical activity and amyloid-β plasma and brain levels: Results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing

Publisher: Springer Science and Business Media LLC

Date: 14-08-2013

DOI: 10.1038/MP.2012.107

Abstract: Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-β (Aβ) and Aβ brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aβ and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aβ levels were measured in fasting blood s les. A subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aβ1-42/1-40 ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aβ from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ε4 carriers. Lower plasma Aβ1-42/1-40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.

Blood-brain barrier–penetrating siRNA nanomedicine for Alzheimer’s disease therapy

Publisher: American Association for the Advancement of Science (AAAS)

Date: 09-10-2020

DOI: 10.1126/SCIADV.ABC7031

Abstract: Glycosylated “triple-interaction” stabilized siRNA nanomedicine ameliorated AD neuropathology by targeting BACE1.

Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

Publisher: Cold Spring Harbor Laboratory

Date: 25-08-2021

DOI: 10.1101/2021.08.20.21261814

Abstract: We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped in iduals from the Busselton Health Study. In our discovery GWAS we identified 667 independent loci associations with these lipid species (479 novel), followed by meta-analysis and validation in two independent cohorts. Lipid endophenotypes (134) identified for CAD were associated with variation at 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 in iduals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P ×10 −3 ), 43 loci were associated with at least one of the 134 lipid endophenotypes. The findings of this study illustrate the value of integrative biology to investigate the genetics and lipid metabolism in the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

Erratum: The AIBL Investigators. Increased risk of cognitive impairment in patients with diabetes is associated with metformin (Diabetes Care (2013) 36 (2981-2987))

Publisher: American Diabetes Association

Date: 17-10-2013

DOI: 10.2337/DC13-ER11B

Copper signaling promotes proteostasis and animal development via allosteric activation of ubiquitin E2D conjugases

Publisher: Cold Spring Harbor Laboratory

Date: 16-02-2021

DOI: 10.1101/2021.02.15.431211

Abstract: Nutrient copper supply is critical for cell growth and differentiation, and its disturbance is associated with major pathologies including cancer and neurodegeneration. Although increasing copper bioavailability in late Precambrian facilitated emergence of novel cuproproteins, their intricate regulation by this essential trace element remains largely cryptic. We found that subtle rises in cellular copper strikingly increase polyubiquitination and accelerate protein degradation within 30 minutes in numerous mammalian cell lines. We track this surprising observation to allostery induced in the UBE2D ubiquitin conjugase clade through a conserved CXXXC sub-femtomolar-affinity Cu + binding motif. Thus, physiologic fluctuation in cytoplasmic Cu + is coupled to the prompt degradation of UBE2D protein targets, including p53. In Drosophila harboring a larval-lethal knockdown of the nearly identical fly orthologue UbcD1, complementation with human UBE2D2 restored near-normal development, but mutation of its CXXXC Cu + binding motif profoundly disrupted organogenesis. Nutrient Cu + emerges as a trophic allosteric modulator of UBE2D activity through a structural motif whose evolution coincides with animal multicellularity. Modulation of nutrient copper impacts protein turnover and animal morphogenesis through conserved allostery of ubiquitin E2D conjugases. Nutrient copper supply is critical for cell growth and differentiation The E2D clade of ubiquitin conjugases contains a sub-femtomolar-affinity Cu + binding motif Allosteric activation by Cu + markedly accelerates protein polyubiquitination This sensor couples physiologic fluctuations in cytoplasmic Cu + with the degradation rate of E2D targets, including p53 This metazoan signaling mechanism is critical for drosophila morphogenesis Conserved allostery of ubiquitin E2D conjugases links nutrient copper signaling to protein degradation and animal morphogenesis.

Current Status of Metals as Therapeutic Targets in Alzheimer's Disease

Publisher: Wiley

Date: 31-07-2003

DOI: 10.1046/J.1532-5415.2003.51368.X

Abstract: There is accumulating evidence that interactions between beta-amyloid and copper, iron, and zinc are associated with the pathophysiology of Alzheimer's disease (AD). A significant dyshomeostasis of copper, iron, and zinc has been detected, and the mismanagement of these metals induces beta-amyloid precipitation and neurotoxicity. Chelating agents offer a potential therapeutic solution to the neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper and zinc chelating agent clioquinol represents a potential therapeutic route that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the accumulation of neocortical beta-amyloid. A Phase II double-blind clinical trial of clioquinol with B12 supplementation will be published soon, and the results are promising. This article summarizes the role of transition metals in amyloidgenesis and reviews the potential promise of chelation therapy as a treatment for AD.

The essential elements of Alzheimer’s disease

Publisher: Elsevier BV

Date: 2021

DOI: 10.1074/JBC.REV120.008207

ATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism

Publisher: Springer Science and Business Media LLC

Date: 29-09-2022

DOI: 10.1007/S13311-022-01300-0

Abstract: Hyposmia is a prevalent prodromal feature of Parkinson’s disease (PD), though the neuropathology that underlies this symptom is poorly understood. Unlike the substantia nigra, the status of metal homeostasis in the olfactory bulbs has not been characterized in PD. Given the increasing interest in metal modulation as a therapeutic avenue in PD, we sought to investigate bulbar metals and the effect of AT434 (formerly PBT434) an orally bioavailable, small molecule modulator of metal homeostasis on hyposmia in a mouse model of parkinsonism (the tau knockout (tau −/− ) mouse). 5.5 (pre-hyposmia) and 13.5-month-old (pre-motor) mice were dosed with ATH434 (30 mg/kg/day, oral gavage) for 6 weeks. Animals then underwent behavioral analysis for olfactory and motor phenotypes. The olfactory bulbs and the substantia nigra were then collected and analyzed for metal content, synaptic markers, and dopaminergic cell number. ATH434 was able to prevent the development of hyposmia in young tau −/− mice, which coincided with a reduction in bulbar iron and copper levels, an increase in synaptophysin, and a reduction in soluble α-synuclein. ATH434 was able to prevent the development of motor impairment in aged tau −/− mice, which coincided with a reduction in iron levels and reduced neurodegeneration in the substantia nigra. These data implicate metal dyshomeostasis in parkinsonian olfactory deficits, and ch ion a potential clinical benefit of ATH434 in both prodromal and clinical stages of PD.

Reduced striatal vesicular monoamine transporter 2 in REM sleep behavior disorder: imaging prodromal parkinsonism

Publisher: Springer Science and Business Media LLC

Date: 23-10-2020

DOI: 10.1038/S41598-020-74495-X

Abstract: Motor deficits in parkinsonism are caused by degeneration of dopaminergic nigral neurons. The success of disease-modifying therapies relies on early detection of the underlying pathological process, leading to early interventions in the disease phenotype. Healthy (n = 16), REM sleep behavior disorder (RBD) (n = 14), dementia with Lewy bodies (n = 10), and Parkinson’s disease (PD) (n = 20) participants underwent 18 F-AV133 vesicular monoamine transporter type-2 (VMAT2) PET to determine the integrity of the nigrostriatal pathway. Clinical, neurophysiological and neuropsychological testing was conducted to assess parkinsonian symptoms. There was reduced VMAT2 levels in RBD participants in the caudate and putamen, indicating nigrostriatal degeneration. RBD patients also presented with hyposmia and anxiety, non-motor symptoms associated with parkinsonism. 18 F-AV133 VMAT2 PET allows identification of underlying nigrostriatal degeneration in RBD patients. These findings align with observations of concurrent non-motor symptoms in PD and RBD participants of the Parkinson’s Progression Markers Initiative. Together, these findings suggest that RBD subjects have prodromal parkinsonism supporting the concept of conducting neuroprotective therapeutic trials in RBD-enriched cohorts. Ongoing longitudinal follow-up of these subjects will allow us to determine the time-window of clinical progression.

Rapid induction of Alzheimer Aβ amyloid formation by zinc

Publisher: American Association for the Advancement of Science (AAAS)

Date: 02-09-1994

DOI: 10.1126/SCIENCE.8073293

Abstract: A beta 1-40, a major component of Alzheimer's disease cerebral amyloid, is present in the cerebrospinal fluid and remains relatively soluble at high concentrations (less than or equal to 3.7 mM). Thus, physiological factors which induce A beta amyloid formation could provide clues to the pathogenesis of the disease. It has been shown that human A beta specifically and saturably binds zinc. Here, concentrations of zinc above 300 nM rapidly destabilized human A beta 1-40 solutions, inducing tinctorial amyloid formation. However, rat A beta 1-40 binds zinc less avidly and is immune to these effects, perhaps explaining the scarcity with which these animals form cerebral A beta amyloid. These data suggest a role for cerebral zinc metabolism in the neuropathogenesis of Alzheimer's disease.

Sensitive, Selective, and Irreversible Inhibition of Cyclooxygenase‐2 Activity by Copper

Publisher: Wiley

Date: 08-02-2008

DOI: 10.1002/CMDC.200700217

The role of metallobiology and amyloid‐β peptides in Alzheimer’s disease

Publisher: Wiley

Date: 28-11-2011

DOI: 10.1111/J.1471-4159.2011.07500.X

Abstract: J. Neurochem. (2012) 120 (Suppl. 1), 149–166. The biggest risk factor for Alzheimer’s disease is the process of ageing, but the mechanisms that lead to the manifestation of the disease remain to be elucidated. Why age triggers the disease is unclear but an emerging theme is the inability for a cell to efficiently maintain many key processes such as energy production, repair, and regenerative mechanisms. Metal ions are essential to the metabolic function of every cell. This review will explore the role and reported changes in metal ions in Alzheimer disease, particularly the brain, blood and cerebral spinal fluid, emphasizing how iron, copper and zinc may be involved through the interactions with amyloid precursor protein, the proteolytically cleaved peptide amyloid‐beta (Aβ), and other related metalloproteins. Finally, we explore the monomeric makeup of possible Aβ dimers, what a dimeric Aβ species from Alzheimer’s disease brain tissue is likely to be composed of, and discuss how metals may influence Aβ production and toxicity via a copper catalyzed dityrosine cross‐link.

Neuroinflammatory responses in the Alzheimer's disease brain promote the oxidative post-translational modification of amyloid deposits

Publisher: Wiley

Date: 28-03-2001

DOI: 10.1002/0470846453.CH32

The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity

Publisher: Wiley

Date: 25-08-2011

DOI: 10.1111/J.1471-4159.2011.07402.X

Abstract: Impaired metal ion homeostasis causes synaptic dysfunction and treatments for Alzheimer's disease (AD) that target metal ions have therefore been developed. The leading compound in this class of therapeutic, PBT2, improved cognition in a clinical trial with AD patients. The aim of the present study was to examine the cellular mechanism of action for PBT2. We show PBT2 induces inhibitory phosphorylation of the α- and β-isoforms of glycogen synthase kinase 3 and that this activity is dependent on PBT2 translocating extracellular Zn and Cu into cells. This activity is supported when Aβ:Zn aggregates are the source of extracellular Zn and adding PBT2 to Aβ:Zn preparations promotes Aβ degradation by matrix metalloprotease 2. PBT2-induced glycogen synthase kinase 3 phosphorylation appears to involve inhibition of the phosphatase calcineurin. Consistent with this, PBT2 increased phosphorylation of other calcineurin substrates, including cAMP response element binding protein and Ca²⁺/calmodulin-dependent protein kinase. These data demonstrate PBT2 can decrease Aβ levels by sequestering the Zn that promotes extracellular formation of protease resistant Aβ:Zn aggregates, and that subsequent intracellular translocation of the Zn by PBT2 induces cellular responses with synapto-trophic potential. Intracellular translocation of Zn and Cu via the metal chaperone activity of PBT2 may be an important mechanism by which PBT2 improves cognitive function in people with AD.

Zinc in neurodegeneration

Publisher: Springer Singapore

Date: 2020

DOI: 10.1007/978-981-15-0557-7_11

Estrogen Decreases Zinc Transporter 3 Expression and Synaptic Vesicle Zinc Levels in Mouse Brain

Publisher: Elsevier BV

Date: 03-2004

DOI: 10.1074/JBC.M309730200

Iron inhibits neurotoxicity induced by trace copper and biological reductants

Publisher: Springer Science and Business Media LLC

Date: 03-02-2004

DOI: 10.1007/S00775-004-0521-8

Abstract: The extracellular microenvironment of the brain contains numerous biological redox agents, including ascorbate, glutathione, cysteine and homocysteine. During ischemia/reperfusion, aging or neurological disease, extracellular levels of reductants can increase dramatically owing to dysregulated homeostasis. The extracellular concentrations of transition metals such as copper and iron are also substantially elevated during aging and in some neurodegenerative disorders. Increases in the extracellular redox capacity can potentially generate neurotoxic free radicals from reduction of Cu(II) or Fe(III), resulting in neuronal cell death. To investigate this in vitro, the effects of extracellular reductants (ascorbate, glutathione, cysteine, homocysteine or methionine) on primary cortical neurons was examined. All redox agents except methionine induced widespread neuronal oxidative stress and subsequent cell death at concentrations occurring in normal conditions or during neurological insults. This neurotoxicity was totally dependent on trace Cu (>or=0.4 microM) already present in the culture medium and did not require addition of exogenous Cu. Toxicity involved generation of Cu(I) and H(2)O(2), while other trace metals did not induce toxicity. Surprisingly, administration of Fe(II) or Fe(III) (>or=2.5 microM) completely abrogated reductant-mediated neurotoxicity. The potent protective activity of Fe correlated with Fe inhibiting reductant-mediated Cu(I) and H(2)O(2) generation in cell-free assays and reduced cellular Cu uptake by neurons. This demonstrates a novel role for Fe in blocking Cu-mediated neurotoxicity in a high reducing environment. A possible pathogenic consequence for these phenomena was demonstrated by abrogation of Fe neuroprotection after pre-exposure of cultures to the Alzheimer's amyloid beta peptide (Abeta). The loss of Fe neuroprotection against reductant toxicity was greater after treatment with human Abeta1-42 than with human Abeta1-40 or rodent Abeta1-42, consistent with the central role of Abeta1-42 in Alzheimer's disease. These findings have important implications for trace biometal interactions and free radical-mediated damage during neurodegenerative illnesses such as Alzheimer's disease and old-age dementia.

Neurodegenerative diseases and oxidative stress

Publisher: Springer Science and Business Media LLC

Date: 03-2004

DOI: 10.1038/NRD1330

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Publisher: Proceedings of the National Academy of Sciences

Date: 13-01-2009

DOI: 10.1073/PNAS.0809057106

Abstract: Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-β (Aβ) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3β (GSK3β) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3β. The strategy involves the use of copper- bis (thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3β through activation of an Akt signaling pathway. Our lead compound Cu II (gtsm) significantly inhibited GSK3β in the brains of APP/PS1 transgenic AD model mice. Cu II (gtsm) also decreased the abundance of Aβ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased Aβ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Aβ trimers and phosphorylated tau.

The Copper bis(thiosemicarbazone) Complex CuII(atsm) Is Protective Against Cerebral Ischemia Through Modulation of the Inflammatory Milieu

Publisher: Springer Science and Business Media LLC

Date: 03-01-2017

DOI: 10.1007/S13311-016-0504-9

Analysis of plasma proteins using 2D gels and novel fluorescent probes: in search of blood based biomarkers for Alzheimer’s disease

Publisher: Springer Science and Business Media LLC

Date: 26-01-2022

DOI: 10.1186/S12953-021-00185-9

Abstract: The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer’s disease. The concentration of proteins in plasma covers a vast range of 12 orders of magnitude. Therefore, to search for medium to low abundant biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma s les from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. We report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE ε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a preliminary validation study, on unique in idual s les compared to the discovery cohort, using a targeted LC-MS/MS assay on a subset of discovered biomarkers. We found that targets that displayed a high degree of isoform specific changes in the 2D gels were not changed in the targeted MS assay which reports on the total level of the biomarker. This demonstrates that further development of mass spectrometry assays is needed to capture the isoform complexity that exists in theses biological s les. However, this study indicates that a peripheral protein signature has potential to aid in the characterization of AD.

Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity

Publisher: Elsevier BV

Date: 12-1999

DOI: 10.1074/JBC.274.52.37111

Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1016/J.NBD.2015.03.015

Abstract: Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12-month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5-month treatment of symptomatic (13 months old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in the hippoc us, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins.

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Publisher: Springer Science and Business Media LLC

Date: 12-07-2016

DOI: 10.1038/MP.2016.96

Abstract: Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T

Poly(2-oxazoline) – Ferrostatin-1 drug conjugates inhibit ferroptotic cell death

Publisher: Elsevier BV

Date: 10-2022

DOI: 10.1016/J.JCONREL.2022.08.004

Abstract: Ferroptosis is a form of non-apoptotic iron induced cell death mechanism implicated in neurodegeneration, yet can be ameliorated with potent radical scavengers such as ferrostatin-1 (Fer-1). Currently, Fer-1 suffers from low water solubility, poor biodistribution profile and is unsuitable for clinical application. Fer-1 polymer-drug conjugates (PDCs) for testing as an anti-ferroptosis therapeutic candidate have yet to be described. Here, we report the synthesis and characterization of a library of water-soluble Fer-1 based poly(2-oxazoline)-drug conjugates. The cationic ring opening polymerization (CROP) of water-soluble 2-oxazoline monomers, and a novel protected aromatic aldehyde 2-oxazoline (DPhOx), produced defined copolymers, which after deprotection were available for modification with Fer-1 via reductive amination and Schiff base chemistry. The conjugates were tested for their activity against RSL3-induced ferroptosis in vitro, and first structure-activity relationships were established. Irreversibly conjugated Fer-1 PDCs possessing an arylamine structural motif showed a greatly increased anti-ferroptosis activity compared to reversibly (Schiff base) linked Fer-1. Overall, this work introduces the first active ferrostatin-PDCs and a new highly tuneable poly(2-oxazoline)-based PDC platform, which provides access to next generation polymeric nanomaterials for anti-ferroptosis applications.

Who's left? Symptoms of schizophrenia that predict clinical trial dropout

Publisher: Wiley

Date: 12-2011

DOI: 10.1002/HUP.1253

Abstract: A significant proportion of subjects drop out of medium to long-term clinical studies prior to trial completion. This may bias reported study outcomes and reduce the statistical power of analyses. There is therefore a need for researchers to better understand the characteristics of dropout populations to increase completion rates. Data from a set of participants recruited as part of a 24-week placebo-controlled trial were used to determine the relationship between the five Lindenmayer factors of positive, negative, cognitive, anxiety/depression and excitement symptoms and dropout at trial completion. Results indicated that the rate of trial dropout was significantly predicted by scores on the negative Lindenmayer factor (X² (6, N = 126) = 15.60, p < .05). By trial completion, participants with 'high' negative Lindenmayer scores dropped out at a rate of 64%, whereas 'medium' and 'low' groups dropped out at 43% and 30%, respectively. No other relationship between symptom severity scores and dropout across the remaining Lindenmayer factors was found. These findings reflect important considerations for the future design of clinical trials involving people with schizophrenia and may also provide clues into treatment compliance issues more generally.

Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C5SC02231B

Abstract: Studying the neuroanatomy of the mouse brain using imaging mass spectrometry and chemometric analysis.

The Impact of N-acetylcysteine on Major Depression: Qualitative Observation and Mixed Methods Analysis of Participant Change during a 12-week Randomised Controlled Trial

Publisher: Korean College of Neuropsychopharmacology

Date: 30-05-2023

DOI: 10.9758/CPN.2023.21.2.320

Chapter 8. Biological Metals: Metallostasis and Alzheimer's Disease

Publisher: Royal Society of Chemistry

Date: 2011

DOI: 10.1039/9781849733014-00152

A protease activity associated with acetylcholinesterase releases the membrane-bound form of the amyloid protein precursor of Alzheimer‘s disease

Publisher: American Chemical Society (ACS)

Date: 11-1991

DOI: 10.1021/BI00108A027

Abstract: Amyloid deposits in the brains of patients with Alzheimer's disease (AD) contain a protein (beta A4) which is abnormally cleaved from a larger transmembrane precursor protein (APP). APP is believed to be normally released from membranes by the action of a protease referred to as APP secretase. Amyloid deposits have also been shown to contain the enzyme acetylcholinesterase (AChE). In this study, a protease activity associated with AChE was found to possess APP secretase activity, stimulating the release of a soluble 100K form of APP from HeLa cells transfected with an APP cDNA. The AChE-associated protease was strongly and specifically inhibited by soluble APP (10 nM) isolated from human brain. The AChE-associated protease cleaved a synthetic beta A4 peptide at the predicted cleavage site. As AChE is decreased in AD, a deficiency of its associated protease might explain why APP is abnormally processed in AD.

A Framework to Objectively Identify Reference Region for Normalizing Quantitative Imaging

Publisher: Springer International Publishing

Date: 2018

DOI: 10.1007/978-3-030-00928-1_8

Characterizing bathocuproine self-association and subsequent binding to Alzheimer's disease amyloidβ-peptide by NMR

Publisher: Wiley

Date: 04-2004

DOI: 10.1002/PSC.539

Abstract: Aggregated amyloid beta-peptide (A beta) is the primary constituent of the extracellular plaques and perivascular amyloid deposits associated with Alzheimer's disease (AD). Deposition of the cerebral amyloid plaques is thought to be central to the disease progression. One such molecule that has previously been shown to 'dissolve' deposited amyloid in post-mortem brain tissue is bathocuproine (BC). In this paper 1H NMR chemical shift analysis and pulsed field gradient NMR diffusion measurements were used to study BC self-association and subsequent binding to A beta. The results show that BC undergoes self-association as its concentration increases. The association constant of BC dimerization, Ka, was estimated to be 0.64 mM(-1) at 25 degrees C from 1H chemical shift analysis. It was also found that dimerization of BC appeared to be essential for its binding to A beta. From the self-association constant of BC, Ka, the fraction of dimeric BC in the complex was obtained and the dissociation constant, Kd, of BC bound to A beta40 peptide was then determined to be approximately 1 mM.

Brain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington’s Disease

Publisher: Springer Science and Business Media LLC

Date: 13-09-2019

DOI: 10.1007/S13311-019-00785-6

GSK-3 in Neurodegenerative Diseases

Publisher: Hindawi Limited

Date: 2011

DOI: 10.4061/2011/189246

Abstract: Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes, and its dysregulation is implicated in the pathogenesis of erse diseases. In this paper we will focus on the dysfunction of GSK-3 in Alzheimer’s disease and Parkinson’s disease. Specifically, GSK-3 is known to interact with tau, β -amyloid (A β ), and α -synuclein, and as such may be crucially involved in both diseases. A β production, for ex le, is regulated by GSK-3, and its toxicity is mediated by GSK-induced tau phosphorylation and degeneration. α -synuclein is a substrate for GSK-3 and GSK-3 inhibition protects against Parkinsonian toxins. Lithium, a GSK-3 inhibitor, has also been shown to affect tau, A β , and α -synuclein in cell culture, and transgenic animal models. Thus, understanding the role of GSK-3 in neurodegenerative diseases will enhance our understanding of the basic mechanisms underlying the pathogenesis of these disorders and also facilitate the identification of new therapeutic avenues.

The effect of dopamine on MPTP-induced rotarod disability

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.NEULET.2013.02.066

Abstract: Dopamine depletion in Parkinson's disease (PD) results in bradykinesia and tremor. Therapeutic administration of the dopamine precursor, l-Dopa, alleviates these symptoms but dyskinesia's can manifest with chronic treatment. In the MPTP toxin mouse model of PD, lesion severity is often assessed by the rotarod behavioral assay. Dopamine depletion by MPTP is thought to induce rotarod behavioral decline. Here we surveyed rotarod behavior and striatal dopamine at timed intervals post-MPTP. Paradoxically, rotarod disability coincided with gradual striatal dopamine restoration. l-Dopa supplementation exacerbated rotarod disability, whereas dopamine antagonism restored performance. dopamine restoration, not depletion, precipitates rotarod disability after MPTP intoxication, and caution should be applied when using this assay for MPTP.

Biometals and Their Therapeutic Implications in Alzheimer’s Disease

Publisher: Springer Science and Business Media LLC

Date: 30-10-2014

DOI: 10.1007/S13311-014-0312-Z

Cysteine oxidation within N-terminal mutant huntingtin promotes oligomerization and delays clearance of soluble protein

Publisher: Elsevier BV

Date: 05-2011

DOI: 10.1074/JBC.M110.199448

Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels

Publisher: Springer Science and Business Media LLC

Date: 03-01-2013

DOI: 10.1038/MP.2011.168

Abstract: The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.

Synaptically released zinc: Physiological functions and pathological effects

Publisher: Springer Science and Business Media LLC

Date: 2001

DOI: 10.1023/A:1012934207456

Abstract: In addition to its familiar role as a component of metalloproteins, zinc is also sequestered in the presynaptic vesicles of a specialized type of neurons called 'zinc-containing' neurons. Here we review the physiological and pathological effects of the release of zinc from these zinc-containing synaptic terminals. The best-established physiological role of synaptically released zinc is the tonic modulation of brain excitability through modulation of amino acid receptors prominent pathological effects include acceleration of plaque deposition in Alzheimer's disease and exacerbation of excitotoxic neuron injury. Synaptically released zinc functions as a conventional synaptic neurotransmitter or neuromodulator, being released into the cleft, then recycled into the presynaptic terminal. Beyond this, zinc also has the highly unconventional property that it passes into postsynaptic neurons during synaptic events, functioning analogously to calcium in this regard, as a transmembrane neural signal. To stimulate comparisons of zinc signals with calcium signals, we have compiled a list of the important parameters of calcium signals and zinc signals. More speculatively, we hypothesize that zinc signals may loosely mimic phosphate 'signals' in the sense that signal zinc ions may commonly bind to proteins in a lasting manner (i.e., 'zincylating' the proteins) with consequential changes in protein structure and function.

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

Publisher: Springer Science and Business Media LLC

Date: 06-06-2022

DOI: 10.1038/S41467-022-30875-7

Abstract: We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 in iduals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 in iduals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association ( P 1 × 10 −3 ), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

Caenorhabditis elegans Maintains Highly Compartmentalized Cellular Distribution of Metals and Steep Concentration Gradients of Manganese

Publisher: Public Library of Science (PLoS)

Date: 29-02-2012

DOI: 10.1371/JOURNAL.PONE.0032685

Glutathione: a novel treatment target in psychiatry

Publisher: Elsevier BV

Date: 07-2008

DOI: 10.1016/J.TIPS.2008.05.001

Abstract: There is accumulating evidence for oxidative stress mechanisms as common pathophysiological pathways in erse psychiatric disorders, which offers novel treatment targets in oxidation biology systems. Of these the glutathione system has the most favourable theoretical foundation, given its dominance as the most generic of cellular antioxidants. Clinically, this hypothesis has been supported by several recently published studies that have reported on the efficacy of N-acetylcysteine, a glutathione precursor, in the treatment of various psychiatric disorders. This article outlines the multidimensional evidence that currently exists for oxidative stress mechanisms in psychiatric disorders and specifically discusses glutathione as a promising novel therapeutic target.

Metallo-pathways to Alzheimer's disease: lessons from genetic disorders of copper trafficking

Publisher: Oxford University Press (OUP)

Date: 2016

DOI: 10.1039/C6MT00095A

Abstract: Copper is an essential metal ion that provides catalytic function to numerous enzymes and also regulates neurotransmission and intracellular signaling. Conversely, a deficiency or excess of copper can cause chronic disease in humans. Menkes and Wilson disease are two rare heritable disorders of copper transport that are characterized by copper deficiency and copper overload, respectively. Changes to copper status are also a common feature of several neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). In the case of AD, which is characterized by brain copper depletion, changes in the distribution of copper has been linked with various aspects of the disease process protein aggregation, defective protein degradation, oxidative stress, inflammation and mitochondrial dysfunction. Although AD is a multifactorial disease that is likely caused by a breakdown in multiple cellular pathways, copper and other metal ions such as iron and zinc play a central role in many of these cellular processes. Pioneering work by researchers who have studied relatively rare copper transport diseases has shed light on potential metal ion related disease mechanisms in other forms of neurodegeneration such as AD.

Metals, Oxidative Stress, and Brain Biology

Publisher: Elsevier

Date: 2010

DOI: 10.1016/B978-012373947-6.00555-9

Discovery of plasma protein biomarkers related to Alzheimer’s disease, sex and APOE genotype

Publisher: Cold Spring Harbor Laboratory

Date: 18-04-2020

DOI: 10.1101/2020.04.15.20066647

Abstract: The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer’s disease. To search for biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3,400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma s les from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. We report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE ε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a validation study on in idual s les using a targeted LC-MS/MS assay. This study indicates that a peripheral protein signature has potential to aid in the characterization of AD. We also found significant associations of protein levels with APOE genotype, indicating that differences in genotype influence the circulating abundances of proteins other than ApoE.

Perturbed iron biology in the prefrontal cortex of people with schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 07-02-2023

DOI: 10.1038/S41380-023-01979-3

Abstract: Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls ( n = 85), among schizophrenia cases ( n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in in iduals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

Combining two large clinical cohorts (AIBL and ADNI) to identify multiple lipid metabolic pathways in prevalent and incident Alzheimer’s disease

Publisher: Cold Spring Harbor Laboratory

Date: 28-05-2020

DOI: 10.1101/2020.05.26.20114215

Abstract: Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising of many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 lipid species across 32 lipid (sub)classes) allows for detailed isomeric and isobaric lipid separation. We applied the methodology to examine plasma s les from the Australian Imaging, Biomarkers and Lifestyle flagship study of aging (AIBL, n = 1112) and serum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 800) studies. Cross sectional analysis using both cohorts identified concordant unique peripheral signatures associated with AD. Specific pathways include sphingolipids, including G M3 gangliosides, where their acyl composition drove the major associations, and lipids previously associated with dysfunctional lipid metabolism in cardiometabolic disease including the phosphatidylethanolamine and triglyceride classes. Infomation derived from improved isomeric seperation highlighted pathway-specific changes with ether lipids including plasmalogens implicating perixosmal dysfunction in disease pathology. Longitudinal analysis revealed similar lipid signitures in both AIBL and ADNI cohorts with future disease onset. We utilised the two independent studies to train and validate multivariate lipid models that significantly improved disease classification and prediction. Together our results provide a holistic view of the lipidome and its relationship with AD using a comprehensive lipidomics approach, providing targets for further mechanistic investigation.

Specific binding of the alzheimer βA4 amyloid precursor to collagen, laminin, and heparin

Publisher: Springer Science and Business Media LLC

Date: 08-1992

DOI: 10.1007/BF01673756

Targeting Transition Metals for Neuroprotection in Alzheimer’s Disease

Publisher: Elsevier

Date: 2017

DOI: 10.1016/B978-0-12-803690-7.00010-7

Preferential Neurodegeneration in the Dentate Gyrus by Amyloid β1–42-Induced Intracellular Zn2+Dysregulation and Its Defense Strategy

Publisher: Springer Science and Business Media LLC

Date: 21-12-2020

DOI: 10.1007/S12035-019-01853-W

Abstract: On the basis of the evidence that rapid intracellular Zn

Cerebrospinal fluid levels of amyloid precursor protein and amyloid β-peptide in Alzheimer‘s disease and major depression - inverse correlation with dementia severity

Publisher: S. Karger AG

Date: 1998

DOI: 10.1159/000007917

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive dementia that ultimately leads to death. Histopathological hallmarks of AD include brain amyloid deposits and neurofibrillary tangles. Major depression is a frequent diagnosis in every gerontopsychiatric clinic that sees patients with both cognitive and affective disorders. Many depressed patients, in fact, are clinically characterized by cognitive impairments. Thus, an assay that excludes – or confirms – probable AD in cognitively impaired patients is desirable. Such assays may use protein markers that are derived from such histopathologically relevant molecules as the amyloid precursor protein (APP) and its derivatives including the amyloid β-peptides (Aβ). To evaluate the differential diagnostic properties of cerebrospinal fluid (CSF) Aβ and secreted soluble ectodomain (APPs), we quantitated CSF levels of these measures in AD patients and compared them to age-matched control patients with major depression. CSF levels of APPs and Aβ were similar in patients with AD or major depression, and the apolipoprotein E genotype had no influence on CSF levels of Aβ in AD patients. Measurement of Aβ peptide using a novel zinc/copper capture ELISA that detects aggregated Aβ peptides as well demonstrated similar levels in AD and major depression. In AD patients, CSF levels of total Aβ (Aβ1–40 plus Aβ1–42) were inversely correlated with a functional measure of dementia severity (NOSGER), suggesting that CSF levels of Aβ decrease with advancing severity of AD. Thus, CSF levels of Aβ are not useful for the differentiation of AD from major depression. However, CSF levels of Aβ reflect the severity of dementia and may be useful as biological markers of the stage of the disease.

Amyloid β1–42-Induced Rapid Zn²⁺ Influx into Dentate Granule Cells Attenuates Maintained LTP Followed by Retrograde Amnesia

Publisher: Springer Science and Business Media LLC

Date: 20-11-2019

DOI: 10.1007/S12035-018-1429-6

Abstract: On the basis of the evidence that amyloid β

Bis(thiosemicarbazone) metal complexes as therapeutics for neurodegenerative diseases

Publisher: Bentham Science Publishers Ltd.

Date: 07-09-2016

DOI: 10.2174/1568026616666160216155746

Abstract: Pathological aggregation of endogenous proteins is a common feature of many neurodegenerative diseases. This is generally accompanied by elevated levels of oxidative stress associated with transition metal dyshomeostasis. As such, strategies targeted toward rectifying metal imbalance are increasingly becoming an attractive therapeutic option. One class of compound showing such therapeutic potential are the bis(thiosemicarbazone) metal complexes. These are small, orally bioavailable compounds capable of crossing the blood brain barrier and capable of delivering bioavailable metal intracellularly. Members of this family of compounds have been shown to successfully treat animal models of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Here we review the current evidence for the efficacy of bis(thiosemicarbazone) metal complexes in treating these diseases and discuss the implications for future development of these compounds.

Delivery of Fluorescent Nanoparticles to the Brain

Publisher: Springer Science and Business Media LLC

Date: 22-09-2016

DOI: 10.1007/S12031-016-0833-5

Abstract: Nanotechnology applications in neuroscience promises to deliver significant scientific and technological breakthroughs, providing answers to unresolved questions regarding the processes occurring in the brain. In this perspective, we provide a short background on two distinct fluorescent nanoparticles and summarize several studies focussed on achieving delivery of these into the brain and their interaction with brain tissue. Furthermore, we discuss challenges and opportunities for further development of nanoparticle-based therapies for targeting delivery of drugs across the blood-brain barrier.

Dimensions of improvement in a clinical trial of N-acetyl cysteine for bipolar disorder

Publisher: Cambridge University Press (CUP)

Date: 04-2011

DOI: 10.1111/J.1601-5215.2011.00530.X

P3-187 Mutagenesis-toxicity studies of the amyloid beta peptide of Alzheimer's disease

Publisher: Elsevier BV

Date: 07-2004

DOI: 10.1016/S0197-4580(04)81339-3

An increased neutrophil-lymphocyte ratio in Alzheimer's disease is a function of age and is weakly correlated with neocortical amyloid accumulation

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.JNEUROIM.2014.05.005

Abstract: Inflammation is a hallmark of Alzheimer's disease (AD). Whether directly involved in the pathogenesis, or a downstream consequence of neuronal death, the blood neutrophil-lymphocyte ratio (NLR) is reported to be a putative, non-invasive peripheral biomarker for AD. The aim of this study was to re-evaluate the diagnostic utility of longitudinal measures of the NLR. The NLR was stable across all time-points and weakly correlated with neocortical amyloid burden (R=0.21 at baseline, 0.27 at 18 months, 0.20 at 36 months and 0.10 at 54 months). Cross-sectionally, the NLR was significantly elevated in AD participants as compared to HC participants at baseline (p<0.0001), 18 months (p 0.05 at all time-points except for 18 months p 0.05) adjusted for age, sex and APOEε4 allele status. Comparing the NLR between cognitive transition groups over time (transition towards an AD type dementia), there was no significant difference in the NLR levels between those participants, who did not transition and those participants who did transition, or those in the stable AD group after adjusting for age, sex and APOEε4 allele status (p>0.05). Despite inflammation being a hallmark in AD and previous reports showing that the NLR can discriminate HC from AD patients, our results suggest that the sensitivity of the NLR itself is not robust enough for diagnostic utility. We identified significant relationships cross sectionally (p 0.5). The NLR also had limited association with cognitive decline, although in our cohort, the number of participants transitioning was relatively small. In conclusion, the NLR may reflect AD-related inflammatory processes in the periphery, but age and sex are dominant covariates which need to be controlled for in population-based screening.

Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study.

Publisher: MDPI AG

Date: 30-04-2022

DOI: 10.3390/BIOMEDICINES10051045

Abstract: Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) in iduals, and the rate of cognitive decline amongst in iduals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF s les of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]± A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03–2.48, p = 0.038). CH participants with CSF NfL cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31–17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL ( median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable in iduals and cognitive decline among those with MCI.

Supranutritional Sodium Selenate Supplementation Delivers Selenium to the Central Nervous System: Results from a Randomized Controlled Pilot Trial in Alzheimer’s Disease

Publisher: Springer Science and Business Media LLC

Date: 13-09-2018

DOI: 10.1007/S13311-018-0662-Z

N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: Relevance to schizophrenia and bipolar disorder

Publisher: Elsevier BV

Date: 07-2011

DOI: 10.1016/J.NEULET.2011.05.027

Abstract: Oxidative stress and reduced brain levels of glutathione have been implicated in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a precursor of glutathione and has additional effects on glutamate neurotransmission, neurogenesis and inflammation. While NAC treatment has shown benefits in both schizophrenia and bipolar disorder, the mechanisms of action are largely unknown. Similarly, the interaction between oxidative stress and altered dopaminergic activities in psychiatric illness is not yet characterized. This study investigated the capacity of NAC in restoring brain glutathione depletion in rats that received 2-cyclohexene-1-one (CHX, 75 mg/kg), d- hetamine (2.5mg/kg) or both. CHX, but not hetamine, induced significant depletion of glutathione levels in the striatum and frontal cortex. Glutathione depletion was reversed by NAC (1000 mg/kg) in saline-treated and hetamine-treated (frontal cortex only) rats. While NAC was shown to be beneficial in this model, the lack of additional glutathione depletion by hetamine in combination with CHX does not support a summative interaction between oxidative stress and altered dopamine transmission.

Ferroptosis and cell death mechanisms in Parkinson's disease

Publisher: Elsevier BV

Date: 03-2017

DOI: 10.1016/J.NEUINT.2017.01.004

Abstract: Symptoms of Parkinson's disease arise due to neuronal loss in multiple brain regions, especially dopaminergic neurons in the substantia nigra pars compacta. Current therapies aim to restore dopamine levels in the brain, but while these provide symptomatic benefit, they do not prevent ongoing neurodegeneration. Preventing neuronal death is a major strategy for disease-modifying therapies however, while many pathogenic factors have been identified, it is currently unknown how neurons die in the disease. Ferroptosis, a recently identified iron-dependent cell death pathway, involves several molecular events that have previously been implicated in PD. This review will discuss ferroptosis and other cell death pathways implicated in PD neurodegeneration, with a focus on the potential to therapeutically target these pathways to slow the progression of this disease.

Effects of N-acetyl cysteine on cognitive function in bipolar disorder

Publisher: Wiley

Date: 10-2012

DOI: 10.1111/J.1440-1819.2012.02392.X

Abstract: Bipolar disorder is characterized by progressive changes in cognition with declines in executive functioning, memory and sustained attention. Current pharmacotherapies for bipolar disorder target mood symptoms but have not addressed these cognitive changes resulting in euthymic in iduals who still experience cognitive deficits. N-acetyl cysteine (NAC) has been shown to have effects on antioxidant status, glutamate transmission, inflammation and neurogenesis. Adjunctive treatment with NAC improves the symptoms experienced by those with bipolar disorder, particularly depression, and it was hypothesized that cognition may also be improved following NAC treatment. As part of a larger randomized, double-blind, placebo-controlled trial, participants in the current report were tested at baseline and 6 months to assess changes in cognitive function following either 2000 mg of NAC daily or placebo. This study failed to find changes in cognitive function following treatment with NAC compared to placebo. While an important pilot study, this study had a small s le size and included a limited battery of cognitive tests. Further investigations on the effects of NAC on cognitive performance in bipolar disorder are required.

The Effects of Clioquinol on P-glycoprotein Expression and Biometal Distribution in the Mouse Brain Microvasculature

Publisher: Elsevier BV

Date: 07-2019

DOI: 10.1016/J.XPHS.2019.01.030

Abstract: Previous studies have demonstrated that the ionophore clioquinol (CQ), in conjunction with the biometals copper and zinc, increases the expression of P-glycoprotein (P-gp) in human cerebral microvascular endothelial (hCMEC/D3) cells. As P-gp expression and function at the blood-brain barrier (BBB) is of great interest regarding CNS drug access and endogenous toxin trafficking (e.g., amyloid beta), the present study assessed the in vivo translation of these previous in vitro findings. Swiss outbred mice received an 11-day treatment of CQ (30 mg/kg) by oral gavage, after which brain microvessel-enriched fractions (MEFs) and surrounding interfaces (subcortical brain tissue and plasma) were extracted. P-gp expression was quantified in the MEF, and biometal concentrations in all 3 compartments were assessed via inductively coupled plasma mass spectrometry. CQ treatment did not modify the expression of P-gp, nor copper or zinc concentrations in the brain MEF under this treatment regime. Metallomic analysis revealed, however, that CQ reduced potassium and magnesium levels in the brain MEF and also lowered brain iron levels. This study has shown that under this dosing regimen, CQ does not increase BBB P-gp expression in Swiss outbred mice, but that CQ facilitates redistribution of certain metal ions within the brain MEF, plasma, and brain parenchyma.

Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging caenorhabditis elegans

Publisher: eLife Sciences Publications, Ltd

Date: 21-07-2020

DOI: 10.7554/ELIFE.56580

Abstract: All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

Decreasing iron neurotoxicity in pantothenate kinase-associated neurodegeneration

Publisher: Elsevier BV

Date: 07-2019

DOI: 10.1016/S1474-4422(19)30193-0

β A4 amyloid protein and its precursor in Alzheimer's disease

Publisher: Elsevier BV

Date: 1992

DOI: 10.1016/0163-7258(92)90039-3

Abstract: The beta A4 amyloid protein is now understood to play a pivotal role in the development of Alzheimer's disease. This protein is generated by the abnormal processing of the amyloid protein precursor, a large membrane glycoprotein. Insights into the mechanisms of this abnormal processing will give information relevant to the design of new therapeutic strategies for Alzheimer's disease.

The Neurophysiology and Pathology of Brain Zinc

Publisher: Society for Neuroscience

Date: 09-11-2011

DOI: 10.1523/JNEUROSCI.3454-11.2011

Abstract: Our understanding of the roles played by zinc in the physiological and pathological functioning of the brain is rapidly expanding. The increased availability of genetically modified animal models, selective zinc-sensitive fluorescent probes, and novel chelators is producing a remarkable body of exciting new data that clearly establishes this metal ion as a key modulator of intracellular and intercellular neuronal signaling. In this Mini-Symposium, we will review and discuss the most recent findings that link zinc to synaptic function as well as the injurious effects of zinc dyshomeostasis within the context of neuronal death associated with major human neurological disorders, including stroke, epilepsy, and Alzheimer's disease.

Rates of diagnostic transition and cognitive change at 18-month follow-up among 1,112 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL)

Publisher: Cambridge University Press (CUP)

Date: 20-11-2013

DOI: 10.1017/S1041610213001956

Abstract: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 in iduals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of in iduals who transitioned to a more severe disease stage compared with those who did not. Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood s le, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging. The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%. There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.

Altered transition metal homeostasis in Niemann-Pick disease, type C1

Publisher: Oxford University Press (OUP)

Date: 2014

DOI: 10.1039/C3MT00308F

Abstract: The Niemann–Pick type C1 disease protein, NPC1 may have a critical role in transition metal homeostasis.

In vivo synaptic activity-independent co-uptakes of amyloid β1–42 and Zn2+ into dentate granule cells in the normal brain

Publisher: Springer Science and Business Media LLC

Date: 24-04-2019

DOI: 10.1038/S41598-019-43012-0

Abstract: Neuronal amyloid β 1–42 (Aβ 1–42 ) accumulation is considered an upstream event in Alzheimer’s disease pathogenesis. Here we report the mechanism on synaptic activity-independent Aβ 1–42 uptake in vivo . When Aβ 1–42 uptake was compared in hippoc al slices after incubating with Aβ 1–42 , In vitro Aβ 1–42 uptake was preferentially high in the dentate granule cell layer in the hippoc us. Because the rapid uptake of Aβ 1–42 with extracellular Zn 2+ is essential for Aβ 1–42 -induced cognitive decline in vivo , the uptake mechanism was tested in dentate granule cells in association with synaptic activity. In vivo rapid uptake of Aβ 1–42 was not modified in the dentate granule cell layer after co-injection of Aβ 1–42 and tetrodotoxin, a Na + channel blocker, into the dentate gyrus. Both the rapid uptake of Aβ 1–42 and Zn 2+ into the dentate granule cell layer was not modified after co-injection of CNQX, an AMPA receptor antagonist, which blocks extracellular Zn 2+ influx, Both the rapid uptake of Aβ 1–42 and Zn 2+ into the dentate granule cell layer was not also modified after either co-injection of chlorpromazine or genistein, an endocytic repressor. The present study suggests that Aβ 1–42 and Zn 2+ are synaptic activity-independently co-taken up into dentate granule cells in the normal brain and the co-uptake is preferential in dentate granule cells in the hippoc us. We propose a hypothesis that Zn-Aβ 1–42 oligomers formed in the extracellular compartment are directly incorporated into neuronal plasma membranes and form Zn 2+ -permeable ion channels.

Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau

Publisher: Public Library of Science (PLoS)

Date: 20-06-2007

DOI: 10.1371/JOURNAL.PONE.0000536

Metals and amyloid-β in Alzheimer's disease

Publisher: Wiley

Date: 24-05-2005

DOI: 10.1111/J.0959-9673.2005.00434.X

Losing my mind - An intimate look at life with Alzheimer's

Publisher: American Association for the Advancement of Science (AAAS)

Date: 28-02-2003

DOI: 10.1126/SCIENCE.1079480

Abstract: Losing My Mind An Intimate Look at Life with Alzheimer's. Thomas DeBaggio. Free Press, New York, 2002. 219 pp. $24, C$36.50. ISBN 0-7432-0565-0. Paper, 222 pp. $13, C$21. ISBN 0-7432-0566-9. Large print, Thorndike, Waterville, ME. 352 pp. $27.95. ISBN 0-7862-4376-7. DeBaggio provides a harrowing first-hand account of the progress of Alzheimer's disease.

Interaction between the zinc(II) and the heparin binding site of the Alzheimer's disease βA4 amyloid precursor protein (APP)

Publisher: Wiley

Date: 28-11-1994

DOI: 10.1016/0014-5793(94)01176-1

Abstract: The Alzheimer's disease beta A4 amyloid precursor protein (APP) has been suggested to be involved in regulation of cell growth, neurite outgrowth and adhesiveness through binding to heparin sulfate proteoglycans. In order to unravel the molecular mechanisms underlying those functions in vitro we show that APP binds in a time dependent and saturable manner to the glycosaminoglycan side-chains of proteoglycans but not to chondroitinsulfate. We also demonstrate an interaction between the high affinity heparin binding site within the carbohydrate domain of APP and the zinc(II) binding site of APP. We show that the affinity for heparin is increased two- to four-fold in the presence of micromolar zinc(II). Thus micromolar concentrations of zinc(II) appear to be able to modulate the binding of APP to heparin side-chains of proteoglycans and as shown previously [Science 265 (1994) 1464-1467] to induce the aggregation of soluble amyloid beta A4 protein.

Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option

Publisher: Cold Spring Harbor Laboratory

Date: 18-04-2020

DOI: 10.1101/2020.04.17.047704

Abstract: The copper compound Cu II (atsm) is in phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu II (atsm) consistently and reproducibly ameliorates neurodegeneration in mutant SOD1 mouse models of ALS where its neuroprotective activity has been ascribed in part to improving availability of copper to essential cuproenzymes. However, SOD1 mutations cause only ~2% of ALS cases with most cases being of unknown aetiology. Therapeutic pertinence of Cu II (atsm) to sporadic ALS is therefore unclear. We assayed post-mortem spinal cord tissue from sporadic cases of ALS for the anatomical and biochemical distribution of copper, the expression of genes involved in copper handling, and the activities of cuproenzymes. The natural distribution of copper is disrupted in sporadic ALS. The ALS-affected tissue has a molecular signature consistent with an unsatiated requirement for copper and cuproenzyme activity is affected. Copper levels are decreased in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Mice expressing mutant SOD1 recapitulate salient features of ALS. The unsatiated requirement for copper that is evident in these mice is a biochemical target for Cu II (atsm). Evidences provided here for disrupted copper bioavailability in human cases of sporadic ALS indicate that a therapeutic mechanism for Cu II (atsm) involving copper bioavailability is pertinent to sporadic cases of ALS, and not just those involving mutant SOD1.

The APOE ε4 Allele Is Associated with Lower Selenium Levels in the Brain: Implications for Alzheimer’s Disease

Publisher: American Chemical Society (ACS)

Date: 03-05-2017

DOI: 10.1021/ACSCHEMNEURO.7B00014

Abstract: The antioxidant activity of selenium, which is mainly conferred by its incorporation into dedicated selenoproteins, has been suggested as a possible neuroprotective approach for mitigating neuronal loss in Alzheimer's disease. However, there is inconsistent information with respect to selenium levels in the Alzheimer's disease brain. We examined the concentration and cellular compartmentalization of selenium in the temporal cortex of Alzheimer's disease and control brain tissue. We found that Alzheimer's disease was associated with decreased selenium concentration in both soluble (i.e., cytosolic) and insoluble (i.e., plaques and tangles) fractions of brain homogenates. The presence of the APOE ε4 allele correlated with lower total selenium levels in the temporal cortex and a higher concentration of soluble selenium. Additionally, we found that age significantly contributed to lower selenium concentrations in the peripheral membrane-bound and vesicular fractions. Our findings suggest a relevant interaction between APOE ε4 and selenium delivery into brain, and show changes in cellular selenium distribution in the Alzheimer's disease brain.

The Caenorhabditis elegans Aβ1–42 Model of Alzheimer Disease Predominantly Expresses Aβ3–42

Publisher: Elsevier BV

Date: 08-2009

DOI: 10.1074/JBC.C109.028514

Mechanisms of amyloid deposition in Alzheimer's disease

Publisher: Wiley

Date: 12-1991

DOI: 10.1111/J.1749-6632.1991.TB00204.X

Abstract: At the cellular level, Alzheimer's disease (AD) must be the result of neuronal dysfunction and degeneration leading to a reduction in synaptic density. Filamentous deposits of amyloid, which define the disease at the molecular level, occur within perikarya, axons, dendrites, and terminals of neurons as neurofibrillary tangles (NFT), in the extracellular neuropil as amyloid plaques (APC), and around blood vessels as amyloid congophilic angiopathy (ACA). These fibrillar amyloid protein aggregates are also found in the brain of all in iduals with Down's syndrome after the age of 30 years. The amyloid deposits apparently occur in the terminal zones of neurons that develop NFT. It is suggested that amyloid deposition is of fundamental significance in AD and that a thorough understanding of amyloid formation will eventually lead to successful therapeutic intervention in AD. As elucidation of the reasons behind amyloid deposition must shed some light on the pathogenesis of AD, we review the current state of knowledge on the nature of the AD amyloid protein, its origin, and its formation. Although there is yet no agreement about the chemical nature of the amyloid protein of NFT, the major constituent of both APC and ACA has been shown to be a 4.5-kD amyloid protein originally termed "beta-protein" or "amyloid A4" which we now denote as "beta A4." Amyloid beta A4 protein is proteolytically derived from a transmembrane protein termed amyloid precursor protein (APP) which is encoded by a widely expressed gene on chromosome 21. Our present results are consistent with the possibility that amyloid formation requires membrane damage or APP molecules that are not or are incorrectly integrated into membranes. To allow the generation of the C-terminus of beta A4, one proteolytic cleavage step has to occur in the sequence that normally forms the transmembrane domain of the APP proteins. This cleavage is crucial for amyloid formation because we could show that the ability of synthetic beta A4 to form amyloid depositions is mainly based on hydrophobic parts of the sequence that have to interact with each other and build up large aggregates under physiologic conditions. Membrane association of APP is expected to interfere with this cleavage and the process of aggregation.

Dietary and lifestyle guidelines for the prevention of Alzheimer's disease

Publisher: Elsevier BV

Date: 09-2014

DOI: 10.1016/J.NEUROBIOLAGING.2014.03.033

Abstract: Risk of developing Alzheimer's disease is increased by older age, genetic factors, and several medical risk factors. Studies have also suggested that dietary and lifestyle factors may influence risk, raising the possibility that preventive strategies may be effective. This body of research is incomplete. However, because the most scientifically supported lifestyle factors for Alzheimer's disease are known factors for cardiovascular diseases and diabetes, it is reasonable to provide preliminary guidance to help in iduals who wish to reduce their risk. At the International Conference on Nutrition and the Brain, Washington, DC, July 19-20, 2013, speakers were asked to comment on possible guidelines for Alzheimer's disease prevention, with an aim of developing a set of practical, albeit preliminary, steps to be recommended to members of the public. From this discussion, 7 guidelines emerged related to healthful diet and exercise habits.

Deserves a hearing? A case report of remitting tinnitus with N-acetyl cysteine

Publisher: African Journals Online (AJOL)

Date: 23-07-2013

DOI: 10.4314/AJPSY.V16I4.31

Predictors of rapid cognitive decline in Alzheimer's disease: Results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing

Publisher: Cambridge University Press (CUP)

Date: 13-07-2012

DOI: 10.1017/S1041610211001335

Abstract: Background: The AIBL study, which commenced in November 2006, is a two-center prospective study of a cohort of 1112 volunteers aged 60+. The cohort includes 211 patients meeting NINCDS-ADRDA criteria for Alzheimer's disease (AD) (180 probable and 31 possible). We aimed to identify factors associated with rapid cognitive decline over 18 months in this cohort of AD patients. Methods: We defined rapid cognitive decline as a drop of 6 points or more on the Mini-Mental State Examination (MMSE) between baseline and 18-month follow-up. Analyses were also conducted with a threshold of 4, 5, 7 and 8 points, as well as with and without subjects who had died or were too severely affected to be interviewed at 18 months and after, both including and excluding subjects whose AD diagnosis was “possible” AD. We sought correlations between rapid cognitive decline and demographic, clinical and biological variables. Results: Of the 211 AD patients recruited at baseline, we had available data for 156 (73.9%) patients at 18 months. Fifty-one patients were considered rapid cognitive decliners (32.7%). A higher Clinical Dementia Rating scale (CDR) and higher CDR “sum of boxes” score at baseline were the major predictors of rapid cognitive decline in this population. Furthermore, using logistic regression model analysis, patients treated with a cholinesterase inhibitor (CheI) had a higher risk of being rapid cognitive decliners, as did males and those of younger age. Conclusions: Almost one third of patients satisfying established research criteria for AD experienced rapid cognitive decline. Worse baseline functional and cognitive status and treatment with a CheI were the major factors associated with rapid cognitive decline over 18 months in this population.

Difference in ability for extracellular Zn2+ influx between human and rat amyloid β1-42 and its significance

Publisher: Elsevier BV

Date: 05-2019

DOI: 10.1016/J.NEURO.2019.01.005

Abstract: The accumulation of amyloid-β

Amyloid beta-Mediated Zn2+ Influx into Dentate Granule Cells Transiently Induces a Short-Term Cognitive Deficit

Publisher: Public Library of Science (PLoS)

Date: 23-12-2014

DOI: 10.1371/JOURNAL.PONE.0115923

Whole-brain metallomic analysis of the common marmoset (Callithrix jacchus)

Publisher: Oxford University Press (OUP)

Date: 2017

DOI: 10.1039/C7MT00012J

Abstract: Despite the importance of transition metals for normal brain function, relatively little is known about the distribution of these elemental species across the different tissue compartments of the primate brain. In this study, we employed laser ablation-inductively coupled plasma-mass spectrometry on PFA-fixed brain sections obtained from two adult common marmosets. Concurrent cytoarchitectonic, myeloarchitectonic, and chemoarchitectonic measurements allowed for identification of the major neocortical, archaecortical, and subcortical isions of the brain, and precise localisation of iron, manganese, and zinc concentrations within each ision. Major findings across tissue compartments included: (1) differentiation of white matter tracts from grey matter based on manganese and zinc distribution (2) high iron concentrations in the basal ganglia, cortex, and substantia nigra (3) co-localization of high concentrations of iron and manganese in the primary sensory areas of the cerebral cortex and (4) high manganese in the hippoc us. The marmoset has become a model species of choice for connectomic, aging, and transgenic studies in primates, and the application of metallomics to these disciplines has the potential to yield high translational and basic science value.

Copper: from neurotransmission to neuroproteostasis

Publisher: Frontiers Media SA

Date: 03-07-2014

DOI: 10.3389/FNAGI.2014.00143

Neurological Dysfunction in Early Maturity of a Model for Niemann–Pick C1 Carrier Status

Publisher: Springer Science and Business Media LLC

Date: 04-03-2016

DOI: 10.1007/S13311-016-0427-5

Intracellular Accumulation of Detergent‐Soluble Amyloidogenic Aβ Fragment of Alzheimer's Disease Precursor Protein in the Hippocampus of Aged Transgenic Mice

Publisher: Wiley

Date: 06-1999

DOI: 10.1046/J.1471-4159.1999.0722479.X

Abstract: To study amyloid beta-protein (A beta) production and aggregation in vivo, we created two transgenic (Tg) mouse lines expressing the C-terminal 100 amino acids of human amyloid precursor protein (APP): Tg C100.V717F and Tg C100.WT. Western blot analysis showed that human APP-C100 and A beta were produced in brain and some peripheral tissues and A beta was produced in serum. Using antibodies specific for the A beta C terminus we found that Tg C100.V717F produced a 1.6-fold increase in A beta42/A beta40 compared with Tg C100.WT. Approximately 30% of total brain A beta (approximately 122 ng/g of wet tissue) was water-soluble. The remaining 70% of A beta partitioned into the particulate fraction and was completely sodium dodecyl sulfate-soluble. In contrast, human Alzheimer's disease brain has predominantly sodium dodecyl sulfate-insoluble A beta. Immunohistochemistry with an A beta(5-8) antibody showed that A beta or A beta-containing fragments accumulated intracellularly in the hippoc us of aged Tg C100.V717F mice. The soluble A beta levels in Tg brain are similar to those in normal human brain, and this may explain the lack of microscopic amyloid deposits in the Tg mice. However, this mouse model provides a system to study the intracellular processing and accumulation of A beta or A beta-containing fragments and to screen for compounds directed at the gamma-secretase activity.

Influence of BDNF Val66Met on the relationship between physical activity and brain volume

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-09-2014

DOI: 10.1212/WNL.0000000000000867

Metal dyshomeostasis and oxidative stress in Alzheimer’s disease

Publisher: Elsevier BV

Date: 04-2013

DOI: 10.1016/J.NEUINT.2012.08.014

Abstract: Alzheimer's disease is the leading cause of dementia in the elderly and is defined by two pathological hallmarks the accumulation of aggregated amyloid beta and excessively phosphorylated Tau proteins. The etiology of Alzheimer's disease progression is still debated, however, increased oxidative stress is an early and sustained event that underlies much of the neurotoxicity and consequent neuronal loss. Amyloid beta is a metal binding protein and copper, zinc and iron promote amyloid beta oligomer formation. Additionally, copper and iron are redox active and can generate reactive oxygen species via Fenton (and Fenton-like chemistry) and the Haber-Weiss reaction. Copper, zinc and iron are naturally abundant in the brain but Alzheimer's disease brain contains elevated concentrations of these metals in areas of amyloid plaque pathology. Amyloid beta can become pro-oxidant and when complexed to copper or iron it can generate hydrogen peroxide. Accumulating evidence suggests that copper, zinc, and iron homeostasis may become perturbed in Alzheimer's disease and could underlie an increased oxidative stress burden. In this review we discuss oxidative/nitrosative stress in Alzheimer's disease with a focus on the role that metals play in this process. Recent studies have started to elucidate molecular links with oxidative/nitrosative stress and Alzheimer's disease. Finally, we discuss metal binding compounds that are designed to cross the blood brain barrier and restore metal homeostasis as potential Alzheimer's disease therapeutics.

Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging

Publisher: Wiley

Date: 22-12-2015

DOI: 10.1016/J.DADM.2015.12.001

Neuroprotective peptide–macrocycle conjugates reveal complex structure–activity relationships in their interactions with amyloid β

Publisher: Oxford University Press (OUP)

Date: 2014

DOI: 10.1039/C4MT00122B

Abstract: Novel neuroprotective peptide–macrocycle conjugates exhibit complex, multifaceted structure–activity relationships in their interactions with amyloid β.

Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid

Publisher: Elsevier BV

Date: 07-0011

DOI: 10.1016/J.NEUROBIOLAGING.2007.10.012

Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting A beta amyloid deposition and toxicity in Alzheimer disease - A pilot phase 2 clinical trial

Publisher: American Medical Association (AMA)

Date: 12-2003

DOI: 10.1001/ARCHNEUR.60.12.1685

Evidence that the β-Amyloid Plaques of Alzheimer's Disease Represent the Redox-silencing and Entombment of Aβ by Zinc

Publisher: Elsevier BV

Date: 06-2000

DOI: 10.1074/JBC.C000165200

Metalloenzyme-like activity of Alzheimer‘s disease β-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2)

Publisher: Elsevier BV

Date: 10-2002

DOI: 10.1074/JBC.M206428200

Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy

Publisher: Elsevier BV

Date: 11-2021

DOI: 10.1016/J.NBD.2021.105509

Abstract: Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.

Erratum to: “Acute phase markers in CSF reveal inflammatory changes in Alzheimer's disease that intersect with pathology, APOE ε4, sex and age” [Prog. Neurobiol. 198 (2021) 101904] (Progress in Neurobiology (2021) 198, (S0301008220301593), (10.1016/j.pneurobio.2020.101904))

Publisher: Elsevier BV

Date: 09-2021

DOI: 10.1016/J.PNEUROBIO.2021.102071

Role of amyloid-β–metal interactions in Alzheimer’s disease

Publisher: Future Medicine Ltd

Date: 09-2011

DOI: 10.2217/FNL.11.43

Abstract: There is an evolving field of metallobiology that has begun to describe a key role for bioavailable metals (particularly copper, zinc and iron) in the pathogenesis of Alzheimer’s disease (AD). In particular, there is an apparent failure in metal ion homeostasis, potentially caused by a pathological mislocalization of the metals in the brain, which appears to be an obligatory step in both the precipitation and potentiation of the disease. A number of both preclinical and clinical studies have also provided a strong burden of proof that normalizing metal ion homeostasis represents a valid therapeutic target, and may indeed represent the first disease-modifying strategy for AD. The role of metals in the pathophysiology of AD will be discussed in this article.

From mouse to mouse‐ear cress: Nanomaterials as vehicles in plant biotechnology

Publisher: Wiley

Date: 08-2021

DOI: 10.1002/EXP.20210002

Abstract: Biological applications of nanomaterials as delivery carriers have been embedded in traditional biomedical research for decades. Despite lagging behind, recent significant breakthroughs in the use of nanocarriers as tools for plant biotechnology have created great interest. In this Perspective, we review the outstanding recent works in nanocarrier‐mediated plant transformation and its agricultural applications. We analyze the chemical and physical properties of nanocarriers determining their uptake efficiency and transport throughout the plant body.

Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice

Publisher: Elsevier BV

Date: 09-1999

DOI: 10.1016/S0006-8993(99)01861-2

Abstract: The pathological process in Alzheimer's disease (AD) involves amyloid beta (Abeta) deposition and neuronal cell degeneration. The neurotoxic Abeta peptide is derived from the amyloid precursor protein (APP), a member of a larger gene family including the amyloid precursor-like proteins, APLP1 and APLP2. The APP and APLP2 molecules contain metal binding sites for copper and zinc. The zinc binding domain (ZnBD) is believed to have a structural rather than a catalytic role. The activity of the copper binding domain (CuBD) is unknown, however, APP reduces copper (II) to copper (I) and this activity could promote copper-mediated neurotoxicity. The expression of APP and APLP2 in the brain suggests they could have an important direct or indirect role in neuronal metal homeostasis. To examine this, we measured copper, zinc and iron levels in the cerebral cortex, cerebellum and selected non-neuronal tissues from APP (APP(-/-)) and APLP2 (APLP2(-/-)) knockout mice using atomic absorption spectrophotometry. Compared with matched wild-type (WT) mice, copper levels were significantly elevated in both APP(-/-) and APLP2(-/-) cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respectively). Copper levels were not significantly different between knockout and WT cerebellum, spleen or serum s les. There were no significant differences observed between APP(-/-), APLP2(-/-) and WT mice zinc or iron levels in any tissue examined. These findings indicate APP and APLP2 expression specifically modulates copper homeostasis in the liver and cerebral cortex, the latter being a region of the brain particularly involved in AD. Perturbations to APP metabolism and in particular, its secretion or release from neurons may alter copper homeostasis resulting in increased Abeta accumulation and free radical generation. These data support a novel mechanism in the APP/Abeta pathway which leads to AD.

Genetic studies of Alzheimer's disease: Lessons learned and future imperatives

Publisher: Elsevier BV

Date: 1994

DOI: 10.1016/0197-4580(94)90193-7

Abstract: To assess long-term oncologic outcomes of robotic-assisted liver resection (RLR) for colorectal cancer (CRC) metastases as compared to a propensity-matched cohort of laparoscopic liver resections (LLR). Although safety and short-term outcomes of RLR have been described and previously compared to LLR, long-term and oncologic data are lacking. A retrospective study was performed of all patients who underwent RLR and LLR for CRC metastases at six high-volume centers in the USA and Europe between 2002 and 2017. Propensity matching was used to match baseline characteristics between the two groups. Data were analyzed with a focus on postoperative and oncologic outcomes, as well as long-term recurrence and survival. RLR was performed in 115 patients, and 514 patients underwent LLR. Following propensity matching 115 patients in each cohort were compared. Perioperative outcomes including mortality, morbidity, reoperation, readmission, intensive care requirement, length-of-stay and margin status were not statistically different. Both prematching and postmatching analyses demonstrated similar overall survival (OS) and disease-free survival (DFS) between RLR and LLR at 5 years (61 vs. 60% OS, p = 0.87, and 38 vs. 31% DFS, p = 0.25, prematching 61 vs. 60% OS, p = 0.78, and 38 vs. 44% DFS, p = 0.62, postmatching). Propensity score matching with a large, multicenter database demonstrates that RLR for colorectal metastases is feasible and safe, with perioperative and long-term oncologic outcomes and survival that are largely comparable to LLR.

Does the FDA‐approved Alzheimer drug aducanumab have a place in the Australian pharmacopoeia?

Publisher: Wiley

Date: 09-02-2022

DOI: 10.5694/MJA2.51408

Correction: Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging

Publisher: Royal Society of Chemistry (RSC)

Date: 2016

DOI: 10.1039/C6SC90060G

Abstract: Correction for ‘Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging’ by Bence Paul et al. , Chem. Sci. , 2015, 6 , 5383–5393.

Enzyme solid-state support assays: a surface plasmon resonance and mass spectrometry coupled study of immobilized insulin degrading enzyme

Publisher: Springer Science and Business Media LLC

Date: 02-12-2008

DOI: 10.1007/S00249-008-0384-Y

Abstract: Solid-support based assays offer several advantages that are not normally available in solution. Enzymes that are anchored on gold surfaces can interact with several different molecules, opening the way to high throughput array format based assays. In this scenario, surface plasmon resonance (SPR) and mass spectrometry (MS) investigations have often been applied to analyze the interaction between immobilized enzyme and its substrate molecules in a tag-free environment. Here, we propose a SPR-MS combined experimental approach aimed at studying insulin degrading enzyme (IDE) immobilized onto gold surfaces and its ability to interact with insulin. The latter is delivered by a microfluidic system to the IDE functionalized surface and the activity of the immobilized enzyme is verified by atmospheric pressure/matrix assisted laser desorption ionization (AP/MALDI) MS analysis. The SPR experiments allow the calculation of the kinetic constants involved for the interaction between immobilized IDE and insulin molecules and evidence of IDE conformational change upon insulin binding is also obtained.

Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β1–42-Induced Excess Zn2+ to Functional Zn2+ Deficiency

Publisher: Springer Science and Business Media LLC

Date: 19-02-2018

DOI: 10.1007/S12035-018-0948-5

Abstract: The role of metallothioneins (MTs) in cognitive decline associated with intracellular Zn

An abnormality of plasma amyloid protein precursor in Alzheimer‘s disease

Publisher: Wiley

Date: 07-1992

DOI: 10.1002/ANA.410320110

Abstract: beta A4 amyloid deposition in the brain, which is characteristic of Alzheimer's disease (AD), may result from either overexpression of the amyloid protein precursor (APP) or failure of APP to be correctly processed. A blood marker reflecting this abnormal metabolism would be of diagnostic value and would provide a means of monitoring the efficacy of therapeutic interventions. We analyzed immunoblots of plasma APP enriched by heparin-Sepharose chromatography from patients with moderate to severe AD dementia (n = 34) and control subjects (n = 77) and found an approximately 50% increase in the proportion of 130-kd APP species in patients with AD (p less than 0.001), no difference in the 110-kd form, a 15 to 30% decrease in the 65-kd form (p less than 0.001), and a 20 to 35% decrease in the proportion of 42-kd APP (p less than 0.001). These species of APP were soluble, lacked the carboxyl terminus, and the 110- and 42-kd species were shown to be consistent with degradation products derived from the 130-kd species. A comparison of levels of 130-kd plasma APP from moderately to severely demented patients with AD and control subjects distinguished the two groups with a specificity of 87.0% and a sensitivity of 79.4%.

Methionine regulates copper/hydrogen peroxide oxidation products of A beta

Publisher: Wiley

Date: 2005

DOI: 10.1002/PSC.626

Abstract: Metal-catalysed oxidation (MCO) may play a causative role in the pathogenesis of Alzheimer's disease (AD). Amyloid beta peptide (Abeta), the major biomarker of AD, in the presence of copper ions reduces Cu(2+) to Cu(+) and catalyses the formation of H(2)O(2) that subsequently induces radicals through Fenton chemistry. Abeta is also subject to attack by free radicals, where the presence of Cu(2+) in conjunction with H(2)O(2) catalyses oxygenation, primarily at the methionine sulfur atom. This work investigates MCO of Abeta, to gain further insight into the role of oxidative stress in AD. By combining a fluorescence assay with gel electrophoresis to monitor MCO reactions of Abeta (1-28) in the presence and absence of methionine it was determined that methionine can both protect some residues against MCO and promote the oxidation of Tyr(10) specifically. Electrospray ionization mass spectrometric analysis of methionine MCO products indicated the formation of methionine sulfoxide, methionine sulfone and related hydroxylated products. Similar products could be formed from the oxidation of Met(35) of Abeta and may relate to changes in properties of the peptide following MCO.

Intracellular copper deficiency increases amyloid-β secretion by diverse mechanisms

Publisher: Portland Press Ltd.

Date: 25-04-2008

DOI: 10.1042/BJ20080103

Abstract: In Alzheimer's disease there is abnormal brain copper distribution, with accumulation of copper in amyloid plaques and a deficiency of copper in neighbouring cells. Excess copper inhibits Aβ (amyloid β-peptide) production, but the effects of deficiency have not yet been determined. We therefore studied the effects of modulating intracellular copper levels on the processing of APP (amyloid precursor protein) and the production of Aβ. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)α into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPβ and produced more amyloidogenic β-cleaved APP C-termini (C99). The level of Aβ secreted from copper-deficient fibroblasts was however regulated and limited by α-secretase cleavage. APP can be processed by both α- and β-secretase, as copper-deficient fibroblasts secreted sAPPβ exclusively, but produced primarily α-cleaved APP C-terminal fragments (C83). Copper deficiency also markedly reduced the steady-state level of APP mRNA whereas the APP protein level remained constant, indicating that copper deficiency may accelerate APP translation. Copper deficiency in human neuroblastoma cells significantly increased the level of Aβ secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Aβ secretion by either influencing APP cleavage or by inhibiting its degradation, with the mechanism dependent on cell type. Overall our results suggest that correcting brain copper imbalance represents a relevant therapeutic target for Alzheimer's disease.

Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice

Publisher: Elsevier BV

Date: 03-2009

DOI: 10.1016/J.BBR.2008.11.017

Abstract: Oxidative stress and reduced brain glutathione (GSH) levels have been reported in psychiatric illnesses including schizophrenia and bipolar disorder. However the role of GSH in cognitive impairment in the illness remains unclear. Treatment of Sprague-Dawley rats and C57Bl/6 mice with 2-cyclohexene-1-one (CHX) dose-dependently reduced striatal and frontal cortical GSH levels similar to those in schizophrenia. In both species, GSH depletion resulted in disruption of short-term spatial recognition memory in a Y-maze test. In conclusion, GSH depletion induces cognitive impairment, which may be relevant to the role of GSH in psychiatric illnesses.

Alzheimer disease-related abnormalities of amyloid β precursor protein isoforms in the platelet: The brain's delegate in the periphery?

Publisher: American Medical Association (AMA)

Date: 09-1998

DOI: 10.1001/ARCHNEUR.55.9.1179

The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease

Publisher: Springer Science and Business Media LLC

Date: 28-06-2017

DOI: 10.1186/S40478-017-0456-2

Abstract: Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology . In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD.

Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients

Publisher: Springer Science and Business Media LLC

Date: 14-11-2008

DOI: 10.1038/SJ.NPP.1301624

Abstract: In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Hippocampal glutathione depletion with enhanced iron level in patients with mild cognitive impairment and Alzheimer’s disease compared with healthy elderly participants

Publisher: Oxford University Press (OUP)

Date: 20-08-2022

DOI: 10.1093/BRAINCOMMS/FCAC215

Abstract: Oxidative stress has been implicated in Alzheimer’s disease, and it is potentially driven by the depletion of primary antioxidant, glutathione, as well as elevation of the pro-oxidant, iron. Present study evaluates glutathione level by magnetic resonance spectroscopy, iron deposition by quantitative susceptibility mapping in left hippoc us, as well as the neuropsychological scores of healthy old participants (N = 25), mild cognitive impairment (N = 16) and Alzheimer’s disease patients (N = 31). Glutathione was found to be significantly depleted in mild cognitive impaired (P & 0.05) and Alzheimer’s disease patients (P & 0.001) as compared with healthy old participants. A significant higher level of iron was observed in left hippoc us region for Alzheimer’s disease patients as compared with healthy old (P & 0.05) and mild cognitive impairment (P & 0.05). Multivariate receiver-operating curve analysis for combined glutathione and iron in left hippoc us region provided diagnostic accuracy of 82.1%, with 81.8% sensitivity and 82.4% specificity for diagnosing Alzheimer’s disease patients from healthy old participants. We conclude that tandem glutathione and iron provides novel avenue to investigate further research in Alzheimer’s disease.

Mounting evidence for the involvement of zinc and copper in Alzheimer's disease

Publisher: Wiley

Date: 07-1999

DOI: 10.1046/J.1365-2362.1999.00472.X

Selective ferroptosis vulnerability due to familial Alzheimer’s disease presenilin mutations

Publisher: Springer Science and Business Media LLC

Date: 21-04-2022

DOI: 10.1038/S41418-022-01003-1

Abstract: Mutations in presenilin 1 and 2 ( PS1 and PS2 ) cause autosomal dominant familial Alzheimer’s disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer’s disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin γ-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.

APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Publisher: Wiley

Date: 25-01-2022

DOI: 10.1002/ALZ.12538

Abstract: The apolipoprotein E ( APOE ) genotype is the strongest genetic risk factor for late‐onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087 the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819 and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. In idual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.

Iron Accumulates in Huntington's Disease Neurons: Protection by Deferoxamine

Publisher: Public Library of Science (PLoS)

Date: 11-10-2013

DOI: 10.1371/JOURNAL.PONE.0077023

Computerised cognitive assessment of concussed Australian Rules footballers

Publisher: BMJ

Date: 10-2001

DOI: 10.1136/BJSM.35.5.354

Abstract: "Paper and pencil" neuropsychological tests play an important role in the management of sports related concussions. They provide objective information on the athlete's cognitive function and thus facilitate decisions on safe return to sport. It has been proposed that computerised cognitive tests have many advantages over such conventional tests, but their role in this domain is yet to be established. To measure cognitive impairment after concussion in a case series of concussed Australian Rules footballers, using both computerised and paper and pencil neuropsychological tests. To investigate the role of computerised cognitive tests in the assessment and follow up of sports related concussions. Baseline measures on the Digit Symbol Substitution Test (DSST), Trail Making Test-Part B (TMT), and a simple reaction time (SRT) test from a computerised cognitive test battery (CogState) were obtained in 240 players. Tests were repeated in players who had sustained a concussive injury. A group of non-injured players were used as matched controls. Six concussions were observed over a period of nine weeks. At the follow up, DSST and TMT scores did not significantly differ from baseline scores in both control and concussed groups. However, analysis of the SRT data showed an increase in response variability and latency after concussion in the injured athletes. This was in contrast with a decrease in response variability and no change in latency on follow up of the control players (p<0.02). Increased variability in response time may be an important cognitive deficit after concussion. This has implications for consistency of an athlete's performance after injury, as well as for tests used in clinical assessment and follow up of head injuries.

Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis

Publisher: Springer Science and Business Media LLC

Date: 13-01-2022

DOI: 10.1007/S12640-021-00455-6

Abstract: The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential environmental etiology factor for some sporadic neurodegenerative diseases. Climate change and eutrophication significantly increase the frequency and intensity of cyanobacterial bloom in water bodies. This review evaluates different neuropathological mechanisms of BMAA at molecular and cellular levels and compares the related studies to provide some useful recommendations. Additionally, the structure and properties of BMAA as well as its microbial origin, especially by gut bacteria, are also briefly covered. Unlike previous reviews, we hypothesize the possible neurotoxic mechanism of BMAA through iron overload. We also discuss the involvement of BMAA in excitotoxicity, TAR DNA-binding protein 43 (TDP-43) translocation and accumulation, tauopathy, and other protein misincorporation and misfolding.

Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease

Publisher: Society for Neuroscience

Date: 31-03-2004

DOI: 10.1523/JNEUROSCI.0297-04.2004

Abstract: Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal β-amyloid deposition is dependent on the activity of zinc transporter 3 (ZnT3), a neocortical synaptic vesicle membrane protein that causes enrichment of exchangeable Zn 2+ in the vesicle, which is externalized on neurotransmission. However, the contribution of zinc to vascular β-amyloid deposition remains unclear. Here, we identify for the first time an exchangeable pool of Zn 2+ in the cerebrovascular wall of normal mice. This histochemically reactive Zn 2+ is enriched in CAA in a transgenic mouse model of AD (Tg2576), and a dramatic reduction of CAA occurs after targeted disruption of the Znt3 gene in these mice. Also, in Znt3 knock-out mice, the amount of exchangeable Zn 2+ [detected by N- (6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide (TFL-Zn)] in the perivascular space was significantly decreased in the neocortex but not in peripheral organs. ZnT3 was not detected in the cerebral vessel walls or in blood components of wild-type mice. Thus, synaptic ZnT3 activity may promote CAA by indirectly raising exchangeable Zn 2+ concentrations in the perivascular spaces of the brain.

The Role of the Plasma Membrane Redox System in the Pathogenesis of Alzheimer’s Disease

Publisher: Humana Press

Date: 2013

DOI: 10.1007/978-1-62703-598-9_6

A mouse model of Alzheimer's disease displays increased susceptibility to kindling and seizure‐associated death

Publisher: Wiley

Date: 16-04-2015

DOI: 10.1111/EPI.12993

Abstract: People with Alzheimer's disease (AD) are up to 10 times more likely to develop epilepsy than the age-matched general population. However, given that only a proportion of patients with AD develop epilepsy, it is likely that additional factors may be required for the epilepsy to emerge. This study aimed to better understand the relationship between AD pathology and seizure susceptibility. It also aimed to investigate a "two-hit" hypothesis for seizure susceptibility through amygdala kindling of rodent AD models. Aged AD mice (Tg2576 model) and wild-type (WT) mice underwent electrical amygdala kindling. Compared with WT mice, Tg2576 mice had significantly lower afterdischarge threshold. Significantly fewer stimulations were required for the Tg2576 mice to reach the first class V seizure. Higher death rate was observed with Tg2576 mice in the kindling group. Both sham and kindled Tg2576 animals had increased levels of sprouting in the supragranular layer of the dentate gyrus compared with the WT counterparts. These findings support the "two-hit" hypothesis and represent a potentially novel research model to help better understand the relationship between AD pathology and epilepsy.

The ubiquitin proteasome system and schizophrenia

Publisher: Elsevier BV

Date: 06-2020

DOI: 10.1016/S2215-0366(19)30520-6

Laser ablation-inductively coupled plasma-mass spectrometry imaging of white and gray matter iron distribution in Alzheimer's disease frontal cortex

Publisher: Elsevier BV

Date: 08-2016

DOI: 10.1016/J.NEUROIMAGE.2016.05.057

Abstract: Iron deposition in the brain is a feature of normal aging, though in several neurodegenerative disorders, including Alzheimer's disease, the rate of iron accumulation is more advanced than in age-matched controls. Using laser ablation-inductively coupled plasma-mass spectrometry imaging we present here a pilot study that quantitatively assessed the iron content of white and gray matter in paraffin-embedded sections from the frontal cortex of Alzheimer's and control subjects. Using the phosphorus image as a confirmed proxy for the white/gray matter boundary, we found that increased intrusion of iron into gray matter occurs in the Alzheimer's brain compared to controls, which may be indicative of either a loss of iron homeostasis in this vulnerable brain region, or provide evidence of increased inflammatory processes as a response to chronic neurodegeneration. We also observed a trend of increasing iron within the white matter of the frontal cortex, potentially indicative of disrupted iron metabolism preceding loss of myelin integrity. Considering the known potential toxicity of excessive iron in the brain, our results provide supporting evidence for the continuous development of novel magnetic resonance imaging approaches for assessing white and gray matter iron accumulation in Alzheimer's disease.

Alzheimer's amyloid beta-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide

Publisher: Elsevier BV

Date: 05-2004

DOI: 10.1016/J.NEUROBIOLAGING.2003.12.027

Vitamin A metabolites inhibit ferroptosis

Publisher: Elsevier BV

Date: 08-2023

DOI: 10.1016/J.BIOPHA.2023.114930

Kalzium Ist Nicht Alles

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.NEURON.2010.01.015

Abstract: Elevation of cerebral Mg2+ with a novel orally delivered ionophore, magnesium threonate, enhances cognition in young and old rats over a 12-24 day treatment interval, as outlined in a paper by Slutsky et al. in this issue of Neuron. Despite both Mg2+ and Zn2+ blocking the NMDA receptor channel, sustained extracellular Mg2+ elevation mimics sustained synaptic Zn2+ concentrations by increasing hippoc al NR2B expression and bouton density.

The effect of paraformaldehyde fixation and sucrose cryoprotection on metal concentration in murine neurological tissue

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C3JA50281C

Accelerated kindling epileptogenesis in Tg4510 tau transgenic mice, but not in tau knockout mice

Publisher: Wiley

Date: 18-03-2020

DOI: 10.1111/EPI.13847

Abstract: The biologic processes underlying epileptogenesis following a brain insult are not fully understood, but several lines of evidence suggest that hyperphosphorylation of tau may be an important factor in these processes. To provide further insight into the causal relationship between tau and epileptogenesis, this study applied amygdala kindling to rTg4510 mice that, concurrent with other pathologies, overexpress phosphorylated tau, tau knockout mice, or their respective wild-type controls. Mice were electrically stimulated twice daily, 5 days per week for 3 weeks. Electroencephalography was recorded to measure the primary afterdischarge duration, and the behavioral progression of kindling-induced seizures was assessed. rTg4510 mice (n = 10) had increased primary afterdischarge durations (p < 0.001), and significantly more rapid progression of kindling (p < 0.001), compared with wild-type mice (n = 10). Tau knockout mice (n = 7), however, did not differ from their wild-type counterparts (n = 8) on any of the seizure outcomes. These results suggest that Tg4510 mice are more vulnerable to epileptogenesis, but that the presence of tau itself is not necessary for kindling epileptogenesis to occur.

Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle

Publisher: Springer Science and Business Media LLC

Date: 06-2021

DOI: 10.1038/S41467-021-23198-6

Abstract: Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.

Mechanisms of Copper Ion Mediated Huntington's Disease Progression

Publisher: Public Library of Science (PLoS)

Date: 28-03-2007

DOI: 10.1371/JOURNAL.PONE.0000334

Is ALS caused by an altered oxidative activity of mutant superoxide dismutase?

Publisher: Springer Science and Business Media LLC

Date: 10-2002

DOI: 10.1038/NN1002-919A

Redox Modulating Factors Affect Longevity Regulation in Rotifers

Publisher: Oxford University Press (OUP)

Date: 27-08-2018

DOI: 10.1093/GERONA/GLY193

Abstract: Rotifers are microinvertebrate models to study the phylogenetically based mechanisms of aging. Our study aimed to develop a physiological system with electron deprivation via a chemical electron carrier/acceptor pair together with extreme caloric restriction (ECR). Middle-aged Philodina acuticornis rotifers were treated with combinations of phenazine methosulfate (PMS, electron carrier) and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT, electron acceptor) for a period of 72 hours under total food deprivation (preselection). The ability of XTT to be reduced was confirmed both in vitro (with NADH) and in vivo (with live rotifers). Subsequently, the respective electron acceptor alone at a lower dose was administered in combination with ECR for several months on preselected survivors. We found that the longevity of rotifers markedly increased (4×) after PMS/XTT/total food deprivation preselection followed by XTT/ECR treatment. Ascorbic acid in equivalent concentrations caused similar but less pronounced tendencies. The synergistic effect of chemical electron deprivation and ECR caused delayed aging and the development of an outstanding phenotype that we refer to as "super rotifers," characterized by increased longevity and retained reproductive ability compared with normal middle-aged in iduals. The presented model provides new insights into the connection between redox modulation and age-related features in vivo.

Clioquinol's return: Cautions from Japan [3]

Publisher: American Association for the Advancement of Science (AAAS)

Date: 22-06-2001

DOI: 10.1126/SCIENCE.292.5525.2251

Redox active metals in neurodegenerative diseases

Publisher: Springer Science and Business Media LLC

Date: 24-10-2019

DOI: 10.1007/S00775-019-01731-9

Abstract: Copper (Cu) and iron (Fe) are redox active metals essential for the regulation of cellular pathways that are fundamental for brain function, including neurotransmitter synthesis and release, neurotransmission, and protein turnover. Cu and Fe are tightly regulated by sophisticated homeostatic systems that tune the levels and localization of these redox active metals. The regulation of Cu and Fe necessitates their coordination to small organic molecules and metal chaperone proteins that restrict their reactions to specific protein centres, where Cu and Fe cycle between reduced (Fe

A Copper Binding Site within the Pathological Conformer Epitope of Mutant SOD1

Publisher: Frontiers Media SA

Date: 2011

DOI: 10.3389/FNINS.2011.00097

Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer‘s amyloidogenesis

Publisher: Elsevier BV

Date: 11-2004

DOI: 10.1016/J.EXGER.2004.08.016

Abstract: A growing body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with APP and Abeta amyloid may contribute to the Alzheimer's amyloid pathology, and thus metal chelation could be a rational therapeutic approach for interdicting AD pathogenesis. However, poor target specificity and consequential clinical safety of current metal-complexing agents have limited their widespread clinical use. To develop the next generation of metal chelators, we have designed and synthesized a new bifunctional molecule-XH1, based on a novel 'pharmacophore conjugation' concept. This lipophilic molecule has both amyloid-binding and metal-chelating moieties covalently connected by amide bonds. It achieved a putative binding geometry with Abeta1-40 peptide by the computational chemistry modeling and reduced Zn(II)-induced Abeta1-40 aggregation in vitro as determined by turbidometry. Moreover, our pilot data indicated that XH1 has no significant neurotoxicity at low micromolar concentrations and acute animal toxicity. XH1 specifically reduced APP protein expression in human SH-SY5Y neuroblastoma cells and attenuated cerebral Abeta amyloid pathology in PS1/APP transgenic mice without inducing apparent toxicity and behavior disturbances. Collectively, these preliminary findings carry implication for XH1 being a BBB-permeable lead compound for AD therapeutics targeting Alzheimer's amyloidogenesis, although further studies are needed.

Relative increase in Alzheimer‘s disease of soluble forms of cerebral Abeta amyloid protein precursor containing the Kunitz protease inhibitory domain

Publisher: Elsevier BV

Date: 02-1998

DOI: 10.1074/JBC.273.9.5013

Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study

Publisher: BMJ

Date: 22-09-2018

DOI: 10.1136/JNNP-2017-316551

Abstract: To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau. Mixed-effects models of CSF Aβ 1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ 1-42 for up to 5 years. In subjects with biomarker-confirmed Alzheimer’s pathology, high CSF ferritin ( .2 ng/mL) was associated with accelerated depreciation of CSF Aβ 1-42 (reporting increased plaque formation p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ 1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer’s subjects from 18.8 to 10.8 years. Iron might facilitate Aβ deposition in Alzheimer’s and accelerate the disease process.

Potential therapeutic targets for Alzheimer's disease

Publisher: Informa Healthcare

Date: 12-2023

DOI: 10.1517/14728222.2.2.157

A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer’s disease

Publisher: American Association for the Advancement of Science (AAAS)

Date: 02-2019

DOI: 10.1126/SCIADV.AAU7220

Abstract: The untargeted discovery and replication of a blood protein panel shows promise for predicting preclinical Alzheimer’s disease.

Tau protein: Relevance to Parkinson's disease

Publisher: Elsevier BV

Date: 11-2010

DOI: 10.1016/J.BIOCEL.2010.07.016

Abstract: Tau is a microtubule-associated protein linked with neurodegenerative diseases. Humans express six different isoforms of tau the longest containing four microtubule-binding repeat motifs in the C-terminal that are vital for what is considered the major biological function of tau, to stabilize microtubules and facilitate axonal transport. The capacity of tau to maintain its normal biological function is dependent upon its phosphorylation state. In Alzheimer's and Parkinson's diseases, there is a hyperphosphorylation of tau that leads to the intracellular accumulation of tau in the form of neurofibrillary tangles. While the role of tau in Parkinson's disease has been understated for some time, here we summarize key genetic, pathological and biochemical evidence supporting a role for tau in the pathogenesis of Parkinson's disease. Toxic interactions with alpha synuclein may lead to hyperphosphorylation of tau and eventually to the deposition of both proteins in the disease.

Qualitative Methods in Early-Phase Drug Trials: Broadening the Scope of Data and Methods From an RCT of N-Acetylcysteine in Schizophrenia

Publisher: Physicians Postgraduate Press, Inc

Date: 21-09-2011

DOI: 10.4088/JCP.09M05741YEL

Brain copper may protect from cognitive decline and Alzheimer’s disease pathology: a community-based study

Publisher: Springer Science and Business Media LLC

Date: 10-2022

DOI: 10.1038/S41380-022-01802-5

Abstract: Copper is an essential micronutrient for brain health and dyshomeostasis of copper could have a pathophysiological role in Alzheimer's disease (AD), however, there are limited data from community-based s les. In this study, we investigate the association of brain copper (assessed using ICP-MS in four regions -inferior temporal, mid-frontal, anterior cingulate, and cerebellum) and dietary copper with cognitive decline and AD pathology burden (a quantitative summary of neurofibrillary tangles, diffuse and neuritic plaques in multiple brain regions) at autopsy examination among deceased participants (N = 657 age of death: 90.2(±6.2)years, 70% women, 25% APOE-ɛ4 carriers) in the Rush Memory and Aging Project. During annual visits, these participants completed cognitive assessments using a 19-test battery and dietary assessments (using a food frequency questionnaire). Regression, linear mixed-effects, and logistic models adjusted for age at death, sex, education, and APOE-ε4 status were used. Higher composite brain copper levels were associated with slower cognitive decline (β(SE) = 0.028(0.01), p = 0.001) and less global AD pathology (β(SE) = -0.069(0.02), p = 0.0004). Participants in the middle and highest tertile of dietary copper had slower cognitive decline (T2vs.T1: β = 0.038, p = 0.0008 T3vs.T1: β = 0.028, p = 0.01) than those in the lowest tertile. Dietary copper intake was not associated with brain copper levels or AD pathology. Associations of higher brain copper levels with slower cognitive decline and with less AD pathology support a role for copper dyshomeostasis in AD pathogenesis and suggest that lower brain copper may exacerbate or indicate disease severity. Dietary and brain copper are unrelated but dietary copper is associated with slower cognitive decline via an unknown mechanism.

Metallostasis in Alzheimer's disease

Publisher: Elsevier BV

Date: 09-2013

DOI: 10.1016/J.FREERADBIOMED.2012.10.558

Abstract: 2012 has been another year in which multiple large-scale clinical trials for Alzheimer's disease (AD) have failed to meet their clinical endpoints. With the social and financial burden of this disease increasing every year, the onus is now on the field of AD researchers to investigate alternative ideas to deliver outcomes for patients. Although several major clinical trials targeting Aβ have failed, three smaller clinical trials targeting metal interactions with Aβ have all shown benefit for patients. Here we review the genetic, pathological, biochemical, and pharmacological evidence that underlies the metal hypothesis of AD. The AD-affected brain suffers from metallostasis, or fatigue of metal trafficking, resulting in redistribution of metals into inappropriate compartments. The metal hypothesis is built upon a triad of transition elements: iron, copper, and zinc. The hypothesis has matured from early investigations showing amyloidogenic and oxidative stress consequences of these metals recently, disease-related proteins, APP, tau, and presenilin, have been shown to have major roles in metal regulation, which provides insight into the pathway of neurodegeneration in AD and illuminates potential new therapeutic avenues.

Copper in the brain and Alzheimer’s disease

Publisher: Springer Science and Business Media LLC

Date: 28-10-2009

DOI: 10.1007/S00775-009-0600-Y

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The brain is particularly vulnerable to oxidative damage induced by unregulated redox-active metals such as copper and iron, and the brains of AD patients display evidence of metal dyshomeostasis and increased oxidative stress. The colocalisation of copper and amyloid beta (Abeta) in the glutamatergic synapse during NMDA-receptor-mediated neurotransmission provides a microenvironment favouring the abnormal interaction of redox-potent Abeta with copper under conditions of copper dysregulation thought to prevail in the AD brain, resulting in the formation of neurotoxic soluble Abeta oligomers. Interactions between Abeta oligomers and copper can further promote the aggregation of Abeta, which is the core component of extracellular amyloid plaques, a central pathological hallmark of AD. Copper dysregulation is also implicated in the hyperphosphorylation and aggregation of tau, the main component of neurofibrillary tangles, which is also a defining pathological hallmark of AD. Therefore, tight regulation of neuronal copper homeostasis is essential to the integrity of normal brain functions. Therapeutic strategies targeting interactions between Abeta, tau and metals to restore copper and metal homeostasis are discussed.

Alzheimer risk factors age and female sex induce cortical Aβ aggregation by raising extracellular zinc

Publisher: Springer Science and Business Media LLC

Date: 09-06-2020

DOI: 10.1038/S41380-020-0800-Y

Generation of soluble oligomeric β-amyloid species via copper catalyzed oxidation with implications for Alzheimer’s disease: A DFT study

Publisher: Springer Science and Business Media LLC

Date: 20-11-2009

DOI: 10.1007/S00894-009-0619-6

Abstract: A mechanism for the oxidation of a dimeric beta-amyloid copper ion complex is proposed based on DFT calculations. It involves the Met35 residue, which is believed to be important in the neurotoxicity causing Alzheimer's disease. Oxidation of Met35 is found to proceed readily with dioxygen when two Met35 residues are close to each other and the copper ion. This indicates that oxidants, such as hydrogen peroxide, are not necessary for oxidation of beta-amyloid copper ion complexes. Understanding these processes could be pivotal in gaining more knowledge of this complex disease and for the development of therapeutic treatments.

Copper, β-amyloid, and Alzheimer's disease: Tapping a sensitive connection

Publisher: Proceedings of the National Academy of Sciences

Date: 23-09-2003

DOI: 10.1073/PNAS.2135061100

Therapeutic treatments for Alzheimer's disease based on metal bioavailability

Publisher: Portico

Date: 2006

DOI: 10.1358/DNP.2006.19.8.1021492

Abstract: The amyloid beta peptide (Abeta) has been widely implicated as a significant causative agent in Alzheimer's disease, although the common mechanistic links between Abeta and other critical elements of Alzheimer's disease, such as advancing age and oxidative stress, are still poorly understood. Here we review data indicating that biometal dyshomeostasis plays a role in these aspects of Alzheimer's disease. Although strong evidence has been published demonstrating a role for iron and zinc in Alzheimer's disease, we have here limited our discussion to data on the role of copper. We also describe how the development of therapeutic agents designed to modulate metal bioavailability has provided promising results in the treatment of Alzheimer's disease. The metal ligand clioquinol has been used successfully in vitro, as well as in animal models and small clinical trials, and a new generation of metal ligand-based therapeutics is under development.

Interaction of glutathione depletion and psychotropic drug treatment in prepulse inhibition in rats and mice

Publisher: Elsevier BV

Date: 12-2010

DOI: 10.1016/J.PBB.2010.08.013

Abstract: Oxidative stress has been implicated in several psychiatric illnesses, including schizophrenia. Glutathione is the brain's primary antioxidant and decreased levels of brain glutathione are reported in schizophrenia. Prepulse inhibition (PPI) is a measure of sensory gating, and PPI is reduced in schizophrenia. This study aimed to investigate the effects of brain glutathione depletion on PPI regulation. Rats and mice were treated with the glutathione-depleting agent, 2-cyclohexene-1-one (CHX), and tested for baseline PPI and its disruption by treatment with hetamine and MK-801. Treatment with CHX caused significant depletion of GSH in frontal cortex and striatum of rats and mice. Baseline PPI and startle were not altered. However, the disruption of PPI after treatment with hetamine was absent in CHX-treated rats. In contrast, the effect of MK-801 was not altered by CHX-treatment, nor was there any effect of CHX treatment in mice. These data show an interaction of glutathione depletion with the effects of hetamine treatment on PPI in rats. This effect could reflect loss of plasticity in PPI regulation caused by the additive effects of CHX-induced glutathione depletion and additional oxidative stress caused by hetamine-induced dopamine release. The significance of these results for schizophrenia is discussed.

Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology

Publisher: Springer Science and Business Media LLC

Date: 18-02-2020

DOI: 10.1038/S41380-019-0375-7

Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice

Publisher: Springer Science and Business Media LLC

Date: 15-08-2018

DOI: 10.1007/S13311-018-0656-X

Ferrous-glutathione coupling mediates ferroptosis and frailty inCaenorhabditis elegans

Publisher: Cold Spring Harbor Laboratory

Date: 31-03-2019

DOI: 10.1101/594408

Abstract: All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis 1 , all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in the Caenorhabditis elegans model of ageing 2 . Here we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan in C. elegans . Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant ageing rate. Because excess age-related iron elevation in somatic tissue, particularly in brain 3–5 , is thought to contribute to degenerative disease 6, 7 , our data indicate that post-developmental interventions to limit ferroptosis may promote healthy ageing.

Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease

Publisher: Portland Press Ltd.

Date: 19-11-2008

DOI: 10.1042/BST0361282

Abstract: The essential metals iron, zinc and copper deposit near the Aβ (amyloid β-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40–42-amino-acid Aβs, which exhibit metal-catalysed neurotoxicity. In health, ubiquitous APP is cleaved in a non-amyloidogenic pathway within its Aβ domain to release the neuroprotective APP ectodomain, APP(s). To adapt and counteract metal-catalysed oxidative stress, as during reperfusion from stroke, iron and cytokines induce the translation of both APP and ferritin (an iron storage protein) by similar mechanisms. We reported that APP was regulated at the translational level by active IL (interleukin)-1 (IL-1-responsive acute box) and IRE (iron-responsive element) RNA stem–loops in the 5′ untranslated region of APP mRNA. The APP IRE is homologous with the canonical IRE RNA stem–loop that binds the iron regulatory proteins (IRP1 and IRP2) to control intracellular iron homoeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability. The APP IRE interacts with IRP1 (cytoplasmic cis-aconitase), whereas the canonical H-ferritin IRE RNA stem–loop binds to IRP2 in neural cell lines, and in human brain cortex tissue and in human blood lysates. The same constellation of RNA-binding proteins [IRP1/IRP2 oly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD.

The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: An open label trial

Publisher: Elsevier BV

Date: 12-2011

DOI: 10.1016/J.JAD.2011.06.005

Abstract: Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders, including bipolar disorder. This dysregulation may be amenable to therapeutic intervention. Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain, and the most generic of all endogenous antioxidants in terms of action. N-acetylcysteine (NAC) is a glutathione precursor that effectively replenishes brain glutathione. Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy, and the limited efficacy of mood stabilisers in the depressive phase of the disorder, this is a major unmet need. This study reports data on the treatment of 149 in iduals with moderate depression during the 2 month open label phase of a randomised placebo controlled clinical trial of the efficacy of 1g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder. In this trial, the estimated mean baseline Bipolar Depression Rating Scale (BDRS) score was 19.7 (SE=0.8), and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 (SE=0.8). This reduction was statistically significant (p<0.001). Improvements in functioning and quality of life were similarly evident. These open label data demonstrate a robust decrement in depression scores with NAC treatment. Large placebo controlled trials of acute bipolar depression are warranted.

Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease.

Publisher: Proceedings of the National Academy of Sciences

Date: 13-05-2008

DOI: 10.1073/PNAS.0800712105

Abstract: Amelyoid-β peptide (Aβ) is a major causative agent responsible for Alzheimer's disease (AD). Aβ contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy. To test this hypothesis, a range of L-PtCl 2 (L = 1,10-phenanthroline derivatives) complexes were examined and shown to bind to Aβ, inhibit neurotoxicity and rescue Aβ-induced synaptotoxicity in mouse hippoc al slices. Coordination of the complexes to Aβ altered the chemical properties of the peptide inhibiting amyloid formation and the generation of reactive oxygen species. In comparison, the classic anticancer drug cisplatin did not affect any of the biochemical and cellular effects of Aβ. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for Aβ onto the platinum complexes. The potent effect of the L-PtCl 2 complexes identifies this class of compounds as therapeutic agents for AD.

Human brain β A4 amyloid protein precursor of Alzheimer‘s disease: purification and partial characterization

Publisher: Wiley

Date: 10-1992

DOI: 10.1111/J.1471-4159.1992.TB08465.X

Abstract: The major component of the amyloid deposition that characterizes Alzheimer's disease is the 4-kDa beta A4 protein, which is derived from a much larger amyloid protein precursor (APP). A procedure for the complete purification of APP from human brain is described. The same amino terminal sequence of APP was found in two patients with Alzheimer's disease and one control subject. Two major forms of APP were identified in human brain with apparent molecular masses of 100-110 kDa and 120-130 kDa. Soluble and membrane fractions of brain contained nearly equal amounts of APP in both humans and rats. Immunoprecipitation with carboxyl terminus-directed antibodies indicates that the soluble forms of APP are truncated. Carboxyl terminus truncation of membrane-associated forms of human brain APP was also found to occur during postmortem autolysis. The availability of purified human brain APP will facilitate the investigation of its normal function and the events that lead to its abnormal cleavage in patients with Alzheimer's disease.

High Content, Multi-Parameter Analyses in Buccal Cells to Identify Alzheimer's Disease

Publisher: Bentham Science Publishers Ltd.

Date: 11-05-2016

DOI: 10.2174/1567205013666160315112151

Abstract: Alzheimer's disease (AD) is a degenerative brain disorder and is the most common form of dementia. Minimally invasive approaches are required that combine biomarkers to identify in iduals who are at risk of developing mild cognitive impairment (MCI) and AD, to appropriately target clinical trials for therapeutic discovery as well as lifestyle strategies aimed at prevention. Buccal mucosa cells from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing cohort (n=60) were investigated for cytological markers that could be used to identify both MCI and AD in iduals. Visual scoring of the buccal cytome demonstrated a significantly lower frequency of basal and karyorrhectic cells in the MCI group compared with controls. A high content, automated assay was developed using laser scanning cytometry to simultaneously measure cell types, nuclear DNA content and aneuploidy, neutral lipid content, putative Tau and amyloid-β (Aβ) in buccal cells. DNA content, aneuploidy, neutral lipids and Tau were similar in all groups. However, there was significantly lower Tau protein in both basal and karyolytic buccal cell types compared with differentiated buccal cells. Aβ, as measured by frequency of cells containing Aβ signal, as well as area and integral of Aβ signal, was significantly higher in the AD group compared with the control group. Buccal cell Aβ was correlated with mini-mental state examination (MMSE) scores (r = -0.436, P=0.001) and several blood-based biomarkers. Combining newly identified biomarkers from buccal cells with those already established may offer a potential route for more specific biomarker panels which may substantially increase the likelihood of better predictive markers for earlier diagnosis of AD.

Metals and neuroscience

Publisher: Elsevier BV

Date: 04-2000

DOI: 10.1016/S1367-5931(99)00073-3

Abstract: Data are now rapidly accumulating to show that metallochemical reactions might be the common denominator underlying Alzheimer's disease, amyotrophic lateral sclerosis, prion diseases, cataracts, mitochondrial disorders and Parkinson's disease. In these disorders, an abnormal reaction between a protein and a redox-active metal ion (copper or iron) promotes the formation of reactive oxygen species or radicalization. It is especially intriguing how the powerful catalytic redox activity of antioxidant Cu/Zn-superoxide dismutase can convert into a pro-oxidant activity, a theme echoed in the recent proposal that Abeta and PrP, the proteins respectively involved in Alzheimer's disease and prion diseases, possess similar redox activities.

Decreased serum zinc is an effect of ageing and not Alzheimer's disease

Publisher: Oxford University Press (OUP)

Date: 2014

DOI: 10.1039/C4MT00060A

Abstract: Serum zinc decreases with age.

P2X7 Receptor-mediated Scavenger Activity of Mononuclear Phagocytes toward Non-opsonized Particles and Apoptotic Cells Is Inhibited by Serum Glycoproteins but Remains Active in Cerebrospinal Fluid

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1074/JBC.M112.340885

The N‐terminal copper‐binding domain of the amyloid precursor protein protects against Cu²⁺neurotoxicity in vivo

Publisher: Wiley

Date: 02-09-2004

DOI: 10.1096/FJ.03-1349FJE

Tau-mediated iron export prevents ferroptotic damage after ischemic stroke

Publisher: Springer Science and Business Media LLC

Date: 08-09-2017

DOI: 10.1038/MP.2017.171

Abstract: Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia-reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia-reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau-iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome.

Selenium mediates exercise-induced adult neurogenesis and reverses learning deficits induced by hippocampal injury and aging

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.CMET.2022.01.005

Abstract: Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed that SEPP1 and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) are required for the exercise-induced increase in adult hippoc al neurogenesis. In vivo selenium infusion increased hippoc al neural precursor cell (NPC) proliferation and adult neurogenesis. Mimicking the effect of exercise through dietary selenium supplementation restored neurogenesis and reversed the cognitive decline associated with aging and hippoc al injury, suggesting potential therapeutic relevance. These results provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippoc al NPCs and their subsequent recruitment into the neurogenic trajectory.

Characterization and identification of dityrosine crosslinked peptides using tandem mass spectrometry

Publisher: American Chemical Society (ACS)

Date: 18-05-2017

DOI: 10.1021/ACS.ANALCHEM.7B00941

Abstract: The use of mass spectrometry coupled with chemical cross-linking of proteins has become a powerful tool for proteins structure and interactions studies. Unlike structural analysis of proteins using chemical reagents specific for lysine or cysteine residues, identification of gas-phase fragmentation patterns of endogenous dityrosine cross-linked peptides have not been investigated. Dityrosine cross-linking in proteins and peptides are clinical markers of oxidative stress, aging, and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. In this study, we investigated and characterized the fragmentation pattern of a synthetically prepared dityrosine cross-linked dimer of Aβ(1-16) using ESI tandem mass spectrometry. We then detailed the fragmentation pattern of dityrosine cross-linked Aβ(1-16), using collision induced dissociation (CID), higher-energy collision induced dissociation (HCD), electron transfer dissociation (ETD), and electron capture dissociation (ECD). Application of these generic fragmentation rules of dityrosine cross-linked peptides allowed for the identification of dityrosine cross-links in peptides of Aβ and α-synuclein generated in vitro by enzymatic peroxidation. We report, for the first time, the dityrosine cross-linked residues in human hemoglobin and α-synuclein under oxidative conditions. Together these tools open up the potential for automated analysis of this naturally occurring post-translation modification in neurodegenerative diseases as well as other pathological conditions.

Correction: Iron Accumulates in Huntington's Disease Neurons: Protection by Deferoxamine

Publisher: Public Library of Science (PLoS)

Date: 13-11-2013

DOI: 10.1371/ANNOTATION/67F555F5-35B7-4468-8BAB-26D518942803

Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal alzheimer's disease: A preliminary study

Publisher: Public Library of Science (PLoS)

Date: 27-01-2014

DOI: 10.1371/JOURNAL.PONE.0086498

Amyloid β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+, ERK1/2 and Clusterin signaling in neurons

Publisher: Wiley

Date: 15-09-2016

DOI: 10.1111/JNC.13760

Abstract: A hallmark of Alzheimer's disease is accumulation of amyloid beta (Aβ) deposits, which are associated with neuronal dysfunction, spine loss, and impaired Ca

Cytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease

Publisher: Elsevier BV

Date: 04-2003

DOI: 10.1016/S0140-6736(03)12981-9

Alzheimer's disease drug discovery targeted to the APP mRNA 5 ' untranslated region

Publisher: Springer Science and Business Media LLC

Date: 08-2002

DOI: 10.1007/S12031-002-0014-6

Abstract: We performed a screen for drugs that specifically interact with the 5' untranslated region of the mRNA coding for the Alzheimer's Amyloid Precursor Protein (APP). Using a transfection based assay, in which APP 5'UTR sequences drive the translation of a downstream luciferase reporter gene, we have been screening for new therapeutic compounds that already have FDA approval and are pharmacologically and clinically well-characterized. Several classes of FDA-pre-approved drugs (16 hits) reduced APP 5'UTR-directed luciferase expression (> 95% inhibition of translation). The classes of drugs include known blockers of receptor ligand interactions, bacterial antibiotics, drugs involved in lipid metabolism, and metal chelators. These APP 5'UTR directed drugs exemplify a new strategy to identify RNA-directed agents to lower APP translation and A beta peptide output for Alzheimer's disease therapeutics.

Novel Fluorinated 8-Hydroxyquinoline Based Metal Ionophores for Exploring the Metal Hypothesis of Alzheimer’s Disease

Publisher: American Chemical Society (ACS)

Date: 14-08-2015

DOI: 10.1021/ACSMEDCHEMLETT.5B00281

Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export

Publisher: Springer Science and Business Media LLC

Date: 29-01-2012

DOI: 10.1038/NM.2613

Abstract: The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.

Iron accumulation in skeletal muscles of old mice is associated with impaired regeneration after ischaemia–reperfusion damage

Publisher: Wiley

Date: 04-03-2021

DOI: 10.1002/JCSM.12685

Abstract: Oxidative stress is implicated in the insidious loss of muscle mass and strength that occurs with age. However, few studies have investigated the role of iron, which is elevated during ageing, in age‐related muscle wasting and blunted repair after injury. We hypothesized that iron accumulation leads to membrane lipid peroxidation, muscle wasting, increased susceptibility to injury, and impaired muscle regeneration. To examine the role of iron in age‐related muscle atrophy, we compared the skeletal muscles of 3‐month‐old with 22‐ to 24‐month‐old 129SvEv FVBM mice. We assessed iron distribution and total elemental iron using laser ablation inductively coupled plasma mass spectrometry and Perls' stain on skeletal muscle cross‐sections. In addition, old mice underwent ischaemia–reperfusion (IR) injury (90 min ischaemia), and muscle regeneration was assessed 14 days after injury. Immunoblotting was used to determine lipid peroxidation (4HNE) and iron‐related proteins. To determine whether muscle iron content can be altered, old mice were treated with deferiprone (DFP) in the drinking water, and we assessed its effects on muscle regeneration after injury. We observed a significant increase in total elemental iron (+43%, P 0.05) and lipid peroxidation (4HNE: +76%, P 0.05) in tibialis anterior muscles of old mice. Iron was further increased after injury (adult: +81%, old: +135%, P 0.05) and associated with increased lipid peroxidation (+41%, P 0.05). Administration of DFP did not impact iron or measures of lipid peroxidation in skeletal muscle or modulate muscle mass. Increased muscle iron concentration and lipid peroxidation were associated with less efficient regeneration, evident from the smaller fibres in cross‐sections of tibialis anterior muscles (−24%, P 0.05) and an increased percentage of fibres with centralized nuclei (+4124%, P 0.05) in muscles of old compared with adult mice. Administration of DFP lowered iron after IR injury (PRE: −32%, P 0.05 and POST: −41%, P 0.05), but did not translate to structural improvements. Muscles from old mice have increased iron levels, which are associated with increased lipid peroxidation, increased susceptibility to IR injury, and impaired muscle regeneration. Our results suggest that iron is involved in effective muscle regeneration, highlighting the importance of iron homeostasis in muscle atrophy and muscle repair.

Rapid Restoration of Cognition in Alzheimer's Transgenic Mice with 8-Hydroxy Quinoline Analogs Is Associated with Decreased Interstitial Aβ

Publisher: Elsevier BV

Date: 07-2008

DOI: 10.1016/J.NEURON.2008.06.018

Abstract: As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

Acute phase markers in CSF reveal inflammatory changes in Alzheimer's disease that intersect with pathology, APOE ε4, sex and age

Publisher: Elsevier BV

Date: 03-2021

DOI: 10.1016/J.PNEUROBIO.2020.101904

Abstract: It is unknown how neuroinflammation may feature in the etiology of Alzheimer's disease (AD). We profiled acute phase response (APR) proteins (α1-antitrypsin, α1-antichymotrypsin, ceruloplasmin, complement C3, ferritin, α-fibrinogen, β-fibrinogen, γ-fibrinogen, haptoglobin, hemopexin) in CSF of 1291 subjects along the clinical and biomarker spectrum of AD to investigate the association between inflammatory changes, disease outcomes, and demographic variables. Subjects were stratified by Aβ

Assessing data assimilation frameworks for using multi-mission satellite products in a hydrological context.

Publisher: Elsevier BV

Date: 2019

DOI: 10.1016/J.SCITOTENV.2018.08.032

Abstract: With a growing number of available datasets especially from satellite remote sensing, there is a great opportunity to improve our knowledge of the state of the hydrological processes via data assimilation. Observations can be assimilated into numerical models using dynamics and data-driven approaches. The present study aims to assess these assimilation frameworks for integrating different sets of satellite measurements in a hydrological context. To this end, we implement a traditional data assimilation system based on the Square Root Analysis (SQRA) filtering scheme and the newly developed data-driven Kalman-Takens technique to update the water components of a hydrological model with the Gravity Recovery And Climate Experiment (GRACE) terrestrial water storage (TWS), and soil moisture products from the Advanced Microwave Scanning Radiometer - Earth Observing System (AMSR-E) and Soil Moisture and Ocean Salinity (SMOS) in a 5-day temporal scale. While SQRA relies on a physical model for forecasting, the Kalman-Takens only requires a trajectory of the system based on past data. We are particularly interested in testing both methods for assimilating different combination of the satellite data. In most of the cases, simultaneous assimilation of the satellite data by either standard SQRA or Kalman-Takens achieves the largest improvements in the hydrological state, in terms of the agreement with independent in-situ measurements. Furthermore, the Kalman-Takens approach performs comparably well to dynamical method at a fraction of the computational cost.

The A β peptide of Alzheimer‘s disease directly produces hydrogen peroxide through metal ion reduction

Publisher: American Chemical Society (ACS)

Date: 27-05-1999

DOI: 10.1021/BI990438F

Ablation of tau causes an olfactory deficit in a murine model of Parkinson’s disease

Publisher: Springer Science and Business Media LLC

Date: 05-07-2018

DOI: 10.1186/S40478-018-0560-Y

Copper modulation as a therapy for Alzheimer's disease?

Publisher: Hindawi Limited

Date: 2011

DOI: 10.4061/2011/370345

Abstract: The role of metals in the pathophysiology of Alzheimer's disease (AD) has gained considerable support in recent years, with both in vitro and in vivo data demonstrating that a mis-metabolism of metal ions, such as copper and zinc, may affect various cellular cascades that ultimately leads to the development and/or potentiation of AD. In this paper, we will provide an overview of the preclinical and clinical literature that specifically relates to attempts to affect the AD cascade by the modulation of brain copper levels. We will also detail our own novel animal data, where we treated APP/PS1 (7-8 months old) mice with either high copper (20 ppm in the drinking water), high cholesterol (2% supplement in the food) or a combination of both and then assessed β -amyloid (A β ) burden (soluble and insoluble A β ), APP levels and behavioural performance in the Morris water maze. These data support an interaction between copper/cholesterol and both A β and APP and further highlight the potential role of metal ion dyshomeostasis in AD.

Ionophore and Biometal Modulation of P-glycoprotein Expression and Function in Human Brain Microvascular Endothelial Cells

Publisher: Springer Science and Business Media LLC

Date: 05-03-2018

DOI: 10.1007/S11095-018-2377-6

Abstract: Biometals such as zinc and copper have been shown to affect tight junction expression and subsequently blood-brain barrier (BBB) integrity. Whether these biometals also influence the expression and function of BBB transporters such as P-glycoprotein (P-gp) however is currently unknown. Using the immortalised human cerebral microvascular endothelial (hCMEC/D3) cell line, an in-cell western assay (alongside western blotting) assessed relative P-gp expression after treatment with the metal ionophore clioquinol and biometals zinc and copper. The fluorescent P-gp substrate rhodamine-123 was employed to observe functional modulation, and inductively coupled plasma mass spectrometry (ICP-MS) provided information on biometal trafficking. A 24-h treatment with clioquinol, zinc and copper (0.5, 0.5 and 0.1 μM) induced a significant upregulation of P-gp (1.7-fold) assessed by in-cell western and this was confirmed with western blotting (1.8-fold increase). This same treatment resulted in a 23% decrease in rhodamine-123 accumulation over a 1 h incubation. ICP-MS demonstrated that while t8his combination treatment had no effect on intracellular zinc concentrations, the treatment significantly enhanced bioavailable copper (4.6-fold). Enhanced delivery of copper to human brain microvascular endothelial cells is associated with enhanced expression and function of the important efflux pump P-gp, which may provide therapeutic opportunities for P-gp modulation.

Molecular cytogenetic analysis of breast cancer cell lines

Publisher: Springer Science and Business Media LLC

Date: 11-2000

DOI: 10.1054/BJOC.2000.1458

CSF ferritin in the clinicopathological progression of Alzheimer's disease and associations with APOE and inflammation biomarkers

Publisher: BMJ

Date: 10-11-2022

DOI: 10.1136/JNNP-2022-330052

Abstract: A putative role for iron in driving Alzheimer’s disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ 42 /t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF s les from BioFINDER (n=1239 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ 42 /t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort. In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%–40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-. CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.

Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline

Publisher: Oxford University Press (OUP)

Date: 24-07-2017

DOI: 10.1093/BRAIN/AWX137

Abstract: See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-β by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-β to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-β load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-β positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippoc al quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [β(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [β(standard error) = -0.139 (0.048), P = 0.004), and attention [β(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [β(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [β(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-β to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-β positron emission tomography to stratify in iduals at risk of decline.

“Emerging Alzheimer’s disease therapies: focusing on the future”

Publisher: Elsevier BV

Date: 11-2002

DOI: 10.1016/S0197-4580(02)00123-9

Abstract: The Center for Neurodegenerative Disease Research (CNDR) organized a 1 day symposium entitled "Emerging Alzheimer's disease Therapies: Focusing On The Future" on November 7th, 2001 at the University of Pennsylvania in Philadelphia, PA. The agenda (Fig. 1) focused on novel therapies for Alzheimer's disease (AD) designed to prevent/eliminate Abeta deposits in the brains of AD patients. While fibrillar Abeta deposits known as senile plaques (SPs) and intraneuronal tau fibrils known as neurofibrillary tangles (NFTs) are diagnostic of AD, >50% of patients with familial or sporadic AD as well as elderly Down's syndrome patients with AD harbor a third type of brain amyloid known as Lewy bodies formed by intraneuronal alpha-synuclein fibrils. Thus, AD is a "triple brain amyloidosis" since three different proteins (tau, alpha-synuclein) or peptide fragments (Abeta) of a larger Abeta precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (NFTs, LBs) and outside (SPs) neurons in AD brains. The symposium is summarized here followed by reviews from symposium speakers who describe potential anti-Abeta therapies some of which are in clinical trials.

Transdermal Application of Soluble CuII(atsm) Increases Brain and Spinal Cord Uptake Compared to Gavage with an Insoluble Suspension

Publisher: Elsevier BV

Date: 2023

DOI: 10.1016/J.NEUROSCIENCE.2022.11.026

Abstract: Cu

Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis

Publisher: Elsevier BV

Date: 05-1998

DOI: 10.1074/JBC.273.21.12817