ORCID Profile
0000-0003-0547-5307
Current Organisations
Tessara Therapeutics
,
Florey Institute of Neuroscience and Mental Health
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C6MT00260A
Abstract: The biological transition metals iron (Fe), copper (Cu) and zinc (Zn) are thought to contribute to the neuronal pathologies that occur following traumatic brain injury (TBI), and indeed our previously published work in young (3 month-old) mice clearly demonstrates a significant spatiotemporal modulation of metals following TBI. Of note, however, is the literature observation that there is both an apparent detrimental effect of aging on TBI outcomes and an alteration in metals and their various transporters with normal advancing age. Therefore, to determine whether there was an interaction between aging, metals and TBI, we have utilised laser ablation-inductively coupled plasma-mass spectrometry to examine the spatial and temporal distribution of Fe, Zn and Cu following an acute controlled cortical impact brain injury in aged (24 months) rodents. The relative abundance of metals in corresponding regions within the ipsilateral and contralateral hemispheres as well as the hippoc us was assessed. Substantial region and time point specific alterations in Fe, Zn and Cu were identified immediately and up to 28 days post-TBI. The data from this follow-up study has also been compared to our previous data from young animals, and aged mice exhibit an appreciably enhanced and persistent elevation of all metals in every region surveyed, with in idual metal disparities at various time points observed post-injury. This may potentially contribute to the acceleration in the onset of cognitive decline and neurological disease that has been observed in the aged population following head trauma.
Publisher: American Chemical Society (ACS)
Date: 10-04-2012
DOI: 10.1021/AC300374X
Abstract: Atlases depicting molecular and functional features of the brain are becoming an integral part of modern neuroscience. In this study we used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICPMS) to quantitatively measure iron (Fe), copper (Cu), and zinc (Zn) levels in a serially sectioned C57BL/6 mouse brain (cerebrum and brainstem). Forty-six sections were analyzed in a single experiment of approximately 158 h in duration. We constructed a 46-plate reference atlas by aligning quantified images of metal distribution with corresponding coronal sections from the Allen Mouse Brain Reference Atlas. The 46 plates were also used to construct three-dimensional models of Fe, Cu, and Zn distribution. This atlas represents the first reconstruction of quantitative trace metal distribution through the brain by LA-ICPMS and will facilitate the study of trace metals in the brain and help to elucidate their role in neurobiology.
Publisher: American Chemical Society (ACS)
Date: 02-02-2018
DOI: 10.1021/ACSCHEMNEURO.7B00517
Abstract: Prion diseases are phenotypically erse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrP
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.
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.
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.
Publisher: Public Library of Science (PLoS)
Date: 23-10-2019
Publisher: Springer Science and Business Media LLC
Date: 13-09-2019
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.
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.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2017
DOI: 10.1038/SREP44426
Abstract: The hippoc us has a significant association with memory, cognition and emotions. The dopaminergic projections from both the ventral tegmental area and substantia nigra are thought to be involved in hippoc al activity. To date, however, few studies have investigated dopaminergic innervation in the hippoc us or the functional consequences of reduced dopamine in disease models. Further complicating this, the hippoc us exhibits anatomical and functional differentiation along its dorso-ventral axis. In this work we investigated the role of dopamine on hippoc al long term potentiation using D- hetamine, which stimulates dopamine release, and also examined how a dopaminergic lesion affects the synaptic transmission across the anatomic sub isions of the hippoc us. Our findings indicate that a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine induced dopaminergic lesion has time-dependent effects and impacts mainly on the ventral region of the hippoc us, consistent with the density of dopaminergic innervation. Treatment with a preferential D 3 receptor agonist pramipexole partly restored normal synaptic transmission and Long-Term Potentiation. These data suggest a new mechanism to explain some of the actions of pramipexole in Parkinson´s disease.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.EXPNEUROL.2012.06.002
Abstract: The beta-amyloid (Aβ) peptide comprises the amyloid plaques that characterise Alzheimer's disease (AD), and is thought to significantly contribute towards disease pathogenesis. Oxidative stress is elevated in the AD brain, and there is substantial evidence that the interaction between Aβ and redox-active copper is a major contributing factor towards oxidative stress in AD. The major findings of this study are that redox-active Cu(II)-Aβ causes pronounced axonal pathology in long-term neuronal cultures, including axonal fragmentation and the formation of hyperphosphorylated tau-immunoreactive axonal swellings. Notably, MAP-2 expressing dendritic processes remain largely un-affected by Cu(II)-Aβ treatment. These dystrophic axonal manifestations resemble some of the characteristic neuritic pathology of the AD brain. We show that Cu(II)-Aβ directly causes formation of intra-axonal swellings via the generation of free radicals and subsequent efflux of K+ out of neurons. In summary, we report that redox-active Cu(II)-Aβ can induce substantial neurodegenerative changes in mature neurons, and may have an important role to play in the slowly progressing pathogenesis of AD.
Publisher: Frontiers Media SA
Date: 22-10-2014
Publisher: Frontiers Media SA
Date: 03-08-2018
Publisher: Wiley
Date: 11-07-2022
DOI: 10.1111/EJN.15752
Abstract: Repetitive mild traumatic brain injury, commonly experienced following sports injuries, results in various secondary injury processes and is increasingly recognised as a risk factor for the development of neurodegenerative conditions such as chronic traumatic encephalopathy, which is characterised by tau pathology. We aimed to characterise the underlying pathological mechanisms that might contribute to the onset of neurodegeneration and behavioural changes in the less-explored subacute (1-month) period following single or repetitive controlled cortical impact injury (five impacts, 48 h apart) in 12-week-old male and female C57Bl6 mice. We conducted motor and cognitive testing, extensively characterised the status of tau and its regulatory proteins via western blot and quantified neuronal populations using stereology. We report that r-mTBI resulted in neurobehavioural deficits, gait impairments and anxiety-like behaviour at 1 month post-injury, effects not seen following a single injury. R-mTBI caused a significant increase in amyloid precursor protein, an increased trend towards tau phosphorylation and significant changes in kinase hosphatase proteins that may promote a downstream increase in tau phosphorylation, but no changes in synaptic or neuroinflammatory markers. Lastly, we report neuronal loss in various brain regions following both single and repeat injuries. We demonstrate herein that repeated impacts are required to promote the initiation of a cascade of biochemical events that are consistent with the onset of neurodegeneration subacutely post-injury. Identifying the timeframe in which these changes occur and the pathological mechanisms involved will be crucial for the development of future therapeutics to prevent the onset or mitigate the progression of neurodegeneration following r-mTBI.
Publisher: Frontiers Media SA
Date: 17-08-2018
Publisher: Elsevier BV
Date: 11-1998
Abstract: We have examined the possible role of metallothionein I/II (MT I/II) in Alzheimer's disease (AD), with a focus on the cellular localization of MT I/II relative to the astrocyte marker, glial fibrillary acidic protein (GFAP). In AD and preclinical AD cases, MT I/II immunolabeling was present in glial cells and did not show a spatial relationship with beta-amyloid plaques or neurofibrillary pathology. There was a six- to sevenfold increase in both MT I/II- and GFAP-labeled cells in the gray matter of AD cases, relative to non-AD cases. However, there was a threefold increase in MT I/II-immunoreactive cells, but not GFAP-labeled cells, in the gray matter of preclinical AD cases compared to non-AD cases. Therefore, the specific increase in MT I/II is associated with the initial stages of the disease process, perhaps due to oxidative stress or the mismetabolism of heavy metals.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2000
Abstract: Cytoskeletal disruption is a key pathological change in numerous human neurodegenerative diseases. We have, therefore, examined the effect of taxol, a microtubule-stabilising agent, on the neuronal response to localised trauma in the central nervous system utilising a rodent experimental model that replicates cytoskeletal alterations which occur in conditions such as Alzheimer's disease and head injury. At 1 day post-injury, 1 mM taxol administration to the damaged neocortex resulted in a statistically significant reduction in the density of abnormal neurites labelled with antibodies to neurofilaments. In addition, there was a relative preservation of MAP2 labelling of dendrites surrounding the injury site in taxol-treated, as compared to vehicle-treated, animals at 1 day post-injury. At 4 days post-injury, however, there was a statistically significant increase in the density of abnormal neurites surrounding the injury site in taxol-treated rats as compared to vehicle-treated animals. The degree of MAP2 labelling was also equally decreased in both vehicle- and taxol-treated animals as compared to normal cortex at this time point. Our data suggest that, in the short term, taxol may be stabilising neuronal microtubules and reducing reactive alterations in axons. After longer periods, however, our data indicate that the stereotypical neuronal reaction to trauma may be abnormally prolonged due to taxol administration, consistent with both in vivo work on taxol intoxication in the injured peripheral nervous system and in vitro culture studies.
Publisher: Oxford University Press (OUP)
Date: 2013
DOI: 10.1039/C2MT20164J
Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent toxin used to selectively destroy dopaminergic neurons in the substantia nigra and induce parkinsonism. MPTP is metabolised to the 1-methyl-4-phenylpyridinium ion (MPP(+)) in glia, after which it enters the neuron via the dopamine transporter and results in elevated levels of oxidative stress. The mechanism through which MPP(+) causes cell death is thought to involve redox-active metals, particularly iron (Fe). This review will examine how cellular metal metabolism is altered following MPTP insult, and how this relates to metal dyshomeostasis in idiopathic Parkinson's disease. This includes both cell damage arising from increased metal concentration, and how metal-binding proteins respond to MPTP-induced neurotoxicity. Implications for using MPTP as a model for human Parkinson's disease will be discussed in terms of cell metallobiology.
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.
Publisher: Cambridge University Press (CUP)
Date: 08-1998
DOI: 10.1017/S095026889800106X
Abstract: Pseudomonas aeruginosa is not generally considered a cause of infectious diarrhoea. However, it was the predominant organism isolated from the faeces of 23 unrelated, hospital outpatients investigated in the course of a year for persistent ( week duration) diarrhoea. To investigate the possible aetiological role of P. aeruginosa , these patient histories were reviewed and a selection of their faecal isolates were investigated in vitro ( n [ges ]10) and in vivo ( n =2) for virulence. The patients had a mean age of 60 years, were receiving antibiotics and/or had an underlying illness. Extensive microbiological investigations identified no other potential or recognized enteropathogen in the faeces of 20 of these patients. More than 40% of the isolates tested were able to adhere to HEp-2 cells and exhibited twitching motility (type IV pili), properties indicative of their ability to colonize the human intestine. Cytotoxic activity was demonstrated in bacterium-free cell supernatants of over 80% of isolates supernatants of four isolates tested in infant mice were weakly enterotoxigenic. Two isolates intragastrically inoculated into clindamycin pre-treated rats established persistent infections and induced signs and symptoms of enteritis. Overall these findings suggest that P. aeruginosa can cause diarrhoea particularly in immunodeficient in iduals.
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
Publisher: Oxford University Press (OUP)
Date: 24-12-2020
DOI: 10.1039/C9MT00267G
Abstract: A dysregulation in the homeostasis of metals such as copper, iron and zinc is speculated to be involved in the pathogenesis of tauopathies, which includes Alzheimer's disease (AD). In particular, there is a growing body of evidence to support a role for iron in facilitating the hyperphosphorylation and aggregation of the tau protein into neurofibrillary tangles (NFTs) – a primary neuropathological hallmark of tauopathies. Therefore, the aim of this study was to characterize the spatial and temporal brain metallomic profile in a mouse model of tauopathy (rTg(tauP301L)4510), so as to provide some insight into the potential interaction between tau pathology and iron. Using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), our results revealed an age-dependent increase in brain iron levels in both WT and rTg(tauP301L)4510 mice. In addition, size exclusion chromatography-ICP-MS (SEC-ICP-MS) revealed significant age-related changes in iron bound to metalloproteins such as ferritin. The outcomes from this study may provide valuable insight into the inter-relationship between iron and tau in ageing and neurodegeneration.
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.
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
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
Publisher: Wiley
Date: 18-11-2009
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.
Publisher: Wiley
Date: 17-07-2000
DOI: 10.1046/J.1440-1681.2000.03292.X
Abstract: 1. Central nerve cells undergo a stereotyped regenerative response following physical injury. 2. This reaction involves adaptive changes within the axon and cell body of origin, directed at sprouting and synaptogenesis. 3. Intimately associated with the regenerative response are specific alterations to cytoskeletal proteins, including the neurofilament (NF) triplet. 4. The morphological and neurochemical alterations to NF within axons following injury are reminiscent of plaque-associated dystrophic neurites (DN) in early Alzheimer's disease (AD). 5. Associated changes in perikaryal NF resemble Alzheimer neurofibrillary tangle pathology, while growth-associated sprouting markers are localized to the abnormal neurites of AD. 6. The present review postulates that beta-amyloid plaques in AD cause physical damage to local nerve cell processes and it is the chronic stimulation of the stereotyped response to injury that results in the end-stage pathology and neurodegeneration associated with AD.
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.
Publisher: Elsevier BV
Date: 2021
Publisher: Frontiers Media SA
Date: 12-06-2014
Publisher: Japanese Society of Toxicology
Date: 2016
DOI: 10.2131/JTS.41.449
Abstract: In patients with Alzheimer's disease, in addition to the core symptoms, i.e., cognitive dysfunction, behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety, and hallucinations are known to occur frequently. Because various environmental factors influence the onset and progression of Alzheimer's disease, in the present study, BPSD-like behavioral abnormality of Amyloid β (Aβ)1-42-injected mice was assessed under social isolation, which induces behavioral abnormality. Aβ protein (500 pmol) was injected into the lateral ventricle of mice, which were in idually housed. Two and three weeks after injection into adult mice, the rate of mice that exhibited aggressive behavior, i.e., biting attacks and wrestling, to the total mice, was markedly increased by Aβ injection. Aβ-injected adult mice also showed anxiety-like behavior, in addition to cognitive decline. Serum corticosterone level was markedly increased by Aβ injection. When excitability of hippoc al neurons was checked using hippoc al slices, KCl-induced presynaptic activity was enhanced in hippoc al slices prepared from Aβ-injected mice. These results suggest that social isolation housing of Aβ1-42-injected adult mice induces BPSD-like behavioral abnormality in addition to cognitive decline. It is likely that behavioral abnormality of Aβ1-42-injected adult mice is associated with excitability of hippoc al glutamatergic neurons, which is associated with the elevated corticosterone level.
Publisher: Elsevier BV
Date: 2004
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.
Publisher: Society for Neuroscience
Date: 26-09-2007
DOI: 10.1523/JNEUROSCI.0630-07.2007
Abstract: Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of α-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Aβ plaques are also present in most DLB cases. The contribution of Aβ to the development of DLB is unclear. [ 11 C]-Pittsburgh compound B ([ 11 C]-PIB) is a thioflavin-T derivative that has allowed in vivo Aβ burden to be quantified using positron emission tomography (PET). [ 11 C]-PIB PET studies have shown similar high cortical [ 11 C]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to α-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human α-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [ 3 H]-PIB binds to α-synuclein fibrils but with lower affinity than that demonstrated/reported for Aβ 1–42 fibrils. Furthermore, [ 3 H]-PIB was observed to bind to Aβ plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Aβ plaque-free (“pure DLB”). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Aβ plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [ 11 C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [ 11 C]-PIB PET studies is largely attributable to PIB binding to Aβ plaques and not Lewy bodies.
Publisher: Public Library of Science (PLoS)
Date: 27-04-2011
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.
Publisher: Frontiers Media SA
Date: 20-12-2018
Publisher: Frontiers Media SA
Date: 25-02-2020
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.
Publisher: Oxford University Press (OUP)
Date: 24-03-2011
DOI: 10.1093/BRAIN/AWR038
Abstract: While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippoc al serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48% P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.
Publisher: Public Library of Science (PLoS)
Date: 02-12-2014
Publisher: Oxford University Press (OUP)
Date: 2018
DOI: 10.1039/C8MT00068A
Abstract: Zinc (Zn) deficiency is a clinical consequence of brain injury that can result in neuropathological outcomes that are exacerbated with age.
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.
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.
Publisher: MDPI AG
Date: 23-11-2017
DOI: 10.3390/IJMS18122506
Publisher: Springer Singapore
Date: 2019
DOI: 10.1007/978-981-13-3681-2_5
Abstract: With an increasingly ageing population that is expected to double by 2050 in the U.S., it is paramount that we further understand the neurological changes that occur during ageing. This is relevant not only in the context of "pathological" ageing, where the development of many neurodegenerative disorders is typically a feature of only the older population (and indeed, age is the primary risk factor for many conditions such as Alzheimer's disease), but also for what is considered to be "normal" or "healthy" ageing. Specifically, a significant proportion of the older population are affected by "age-related cognitive decline" (ARCD), which is both independent of dementia and has an incidence 70% higher than dementia alone. However, whilst it is reported that there are pathogenic and phenotypic overlaps between healthy and pathological ageing, it is clear that there is a need to identify the pathways and understand the mechanisms that contribute to this loss of cognitive function with normal ageing, particularly in light of the increasing life expectancy of the global population. Importantly, there is an increasing body of evidence implicating zinc homeostasis as a key player in learning and memory and also potentially ARCD. Further research will ultimately contribute to the development of targeted therapeutics that will promote successful brain ageing. In this chapter we will explore the notion of ARCD, with a perspective on potential key neurochemical pathways that can be targeted for future intervention.
Publisher: Oxford University Press (OUP)
Date: 24-01-2020
DOI: 10.1002/BJS.11422
Abstract: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien–Dindo classification system. A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4–7) and 7 (6–8) days respectively (P & 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46 P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent major 3·3 versus 3·4 per cent P = 0·110). Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.ARR.2017.03.007
Abstract: The primary causative event in the development of prion diseases is the misfolding of the normal prion protein (PrP
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.
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1016/S0301-0082(99)00023-4
Abstract: Alzheimer's disease is associated with a specific pattern of pathological changes in the brain that result in neurodegeneration and the progressive development of dementia. Pathological hallmarks common to the disease include beta-amyloid plaques, dystrophic neurites associated with plaques and neurofibrillary tangles within nerve cell bodies. The exact relationship between these pathological features has been elusive, although it is clear that beta-amyloid plaques precede neurofibrillary tangles in neocortical areas. Examination of the brains of in iduals in the preclinical stage of the disease have shown that the earliest form of neuronal pathology associated with beta-amyloid plaques resembles the cellular changes that follow structural injury to axons. Thus, the development of beta-amyloid plaques in the brain may cause physical damage to axons, and the abnormally prolonged stimulation of the neuronal response to this kind of injury ultimately results in the profound cytoskeletal alterations that underlie neurofibrillary pathology and neurodegeneration. Therapeutically, inhibition of the neuronal reaction to physical trauma may be a useful neuroprotective strategy in the earliest stages of Alzheimer's disease.
Publisher: Frontiers Media SA
Date: 2012
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.
Publisher: Society for Neuroscience
Date: 27-04-2005
DOI: 10.1523/JNEUROSCI.0496-05.2005
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset rogression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-β (Aβ) plaques in the frontal cortex (38% p = 0.018), the cortex at the level of the hippoc us (53% p = 0.0003), and the hippoc us (40% p = 0.06). This was associated with decreased cortical Aβ1-40 (35% p = 0.005) and Aβ1-42 (22% p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for α-C-terminal fragment (α-CTF), 54% and p = 0.04 for β-CTF, 35% and p = 0.03]. This effect was independent of mRNA rotein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant ( p 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.
Publisher: Society for Neuroscience
Date: 26-06-2017
Publisher: MDPI AG
Date: 28-01-2020
DOI: 10.3390/IJMS21030839
Abstract: Metals are critical cellular elements that are involved in a variety of cellular processes, with recent literature demonstrating that zinc, and the synaptic zinc transporter (ZnT3), are specifically involved in learning and memory and may also be key players in age-related neurodegenerative disorders such as Alzheimer’s disease. Whilst the cellular content and location of metals is critical, recent data has demonstrated that the metalation state of proteins is a determinant of protein function and potential toxicity. As we have previously reported that ZnT3 knockout (KO) mice have deficits in total zinc levels at both 3 and 6 months of age, we were interested in whether there might be changes in the metalloproteomic profile in these animals. To do this, we utilised size exclusion chromatography-inductively coupled plasma mass spectrometry (SEC-ICP-MS) and examined hippoc al homogenates from ZnT3 KO and age-matched wild-type mice at 3, 6 and 18 months of age. Our data suggest that there are alterations in specific metal binding proteins, for zinc, copper and iron all being modulated in the ZnT3 KO mice compared to wild-type (WT). These data suggest that ZnT3 KO mice may have impairments in the levels or localisation of multiple transition metals, and that copper- and iron-dependent cellular pathways may also be impacted in these mice.
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.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2007
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.NEUROBIOLAGING.2007.09.003
Abstract: The morphology and neurochemistry of beta-amyloid (A beta) plaque-associated dystrophic neurites present in TgCRND8 and Tg2576 mice was demonstrated to be strikingly similar to that observed in pathologically aged human cases, but not in Alzheimer's disease (AD) cases. Specifically, pathologically aged cases and both transgenic mouse lines exhibited alpha-internexin- and neurofilament-triplet-labelled ring- and bulb-like dystrophic neurites, but no classical hyperphosphorylated-tau dystrophic neurite pathology. In contrast, AD cases demonstrated abundant classical hyperphosphorylated-tau-labelled dystrophic neurites, but no neurofilament-triplet-labelled ring-like dystrophic neurites. Importantly, quantitation demonstrated that the A beta plaques in TgCRND8 mice were highly axonopathic, and localised displacement or clipping of apical dendrite segments was also associated with A beta plaques in both transgenic mouse models. These results suggest that neuronal pathology in these mice represent an accurate and valuable model for understanding, and developing treatments for, the early brain changes of AD.
Publisher: Wiley
Date: 09-07-2018
DOI: 10.1111/CODI.14292
Abstract: Previous studies reported conflicting evidence on the effects of obesity on outcomes after gastrointestinal surgery. The aims of this study were to explore the relationship of obesity with major postoperative complications in an international cohort and to present a meta-analysis of all available prospective data. This prospective, multicentre study included adults undergoing both elective and emergency gastrointestinal resection, reversal of stoma or formation of stoma. The primary end-point was 30-day major complications (Clavien-Dindo Grades III-V). A systematic search was undertaken for studies assessing the relationship between obesity and major complications after gastrointestinal surgery. In idual patient meta-analysis was used to analyse pooled results. This study included 2519 patients across 127 centres, of whom 560 (22.2%) were obese. Unadjusted major complication rates were lower in obese vs normal weight patients (13.0% vs 16.2%, respectively), but this did not reach statistical significance (P = 0.863) on multivariate analysis for patients having surgery for either malignant or benign conditions. In idual patient meta-analysis demonstrated that obese patients undergoing surgery for malignancy were at increased risk of major complications (OR 2.10, 95% CI 1.49-2.96, P < 0.001), whereas obese patients undergoing surgery for benign indications were at decreased risk (OR 0.59, 95% CI 0.46-0.75, P < 0.001) compared to normal weight patients. In our international data, obesity was not found to be associated with major complications following gastrointestinal surgery. Meta-analysis of available prospective data made a novel finding of obesity being associated with different outcomes depending on whether patients were undergoing surgery for benign or malignant disease.
Publisher: Public Library of Science (PLoS)
Date: 31-05-2013
Publisher: Wiley
Date: 14-10-2023
DOI: 10.1111/BPH.15950
Abstract: Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest as iron deposition has been detected in the injured brain in the weeks to months post-TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity and whether this is a cause or consequence of the long-term effects of TBI remains unknown. We investigated the role of iron and the effect of therapeutic intervention using a brain-permeable iron chelator, deferiprone, in a controlled cortical impact mouse model of TBI. An extensive assessment of cognitive, motor and anxiety/depressive outcome measures were examined, and neuropathological and biochemical changes, over a 3-month period post-TBI. Lesion volume was significantly reduced at 3 months, which was preceded by a reduction in astrogliosis, microglia/macrophages and preservation of neurons in the injured brain at 2 weeks and/or 1 month post-TBI in mice receiving oral deferiprone. Deferiprone treatment showed significant improvements in neurological severity scores, locomotor/gait performance and cognitive function, and attenuated anxiety-like symptoms post-TBI. Deferiprone reduced iron levels, lipid peroxidation/oxidative stress and altered expression of neurotrophins in the injured brain over this period. Our findings support a detrimental role of iron in the injured brain and suggest that deferiprone (or similar iron chelators) may be promising therapeutic approaches to improve survival, functional outcomes and quality of life following TBI.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.NEURO.2019.01.005
Abstract: The accumulation of amyloid-β
Publisher: Xia & He Publishing
Date: 02-2005
DOI: 10.3727/000000005783992115
Abstract: There is growing evidence that exercise benefits recovery of neuromuscular function from spinal cord injury (SCI). However, the effect of exercise on gene expression in the spinal cord is poorly understood. We used oligonucleotide microarrays to compare thoracic and lumbar regions of spinal cord of either exercising (voluntary wheel running for 21 days) or sedentary rats. The expression data were filtered using statistical tests for significance, and K-means clustering was then used to segregate lists of significantly changed genes into sets based upon expression patterns across all experimental groups. Levels of brain-derived neurotrophic factor (BDNF) protein were also measured after voluntary exercise, across different regions of the spinal cord. BDNF mRNA increased with voluntary exercise, as has been previously shown for other forms of exercise, contributed to by increases in both exon I and exon III. The exercise-induced gene expression changes identified by microarray analysis are consistent with increases in pathways promoting neuronal health, signaling, remodeling, cellular transport, and development of oligodendrocytes. Taken together these data suggest cellular pathways through which exercise may promote recovery in the SCI population.
Publisher: Public Library of Science (PLoS)
Date: 23-12-2014
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.
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.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C5MT00234F
Abstract: A LA-ICP-MS time course study of changing metal concentrations following traumatic brain injury in mice.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Wiley
Date: 24-11-2004
DOI: 10.1046/J.1471-4159.2003.02193.X
Abstract: Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CNS. In this regard, we have recently demonstrated that MT-IIA (the major human MT-I/-II isoform) promotes neural recovery following focal cortical brain injury. To further investigate the role of MTs in cortical brain injury, MT-I/-II expression was examined in several different experimental models of cortical neuron injury. While MT-I/-II immunoreactivity was not detectable in the uninjured rat neocortex, by 4 days, following a focal cortical brain injury, MT-I/-II was found in astrocytes aligned along the injury site. At latter time points, astrocytes, at a distance up to several hundred microns from the original injury tract, were MT-I/-II immunoreactive. Induced MT-I/-II was found both within the cell body and processes. Using a cortical neuron/astrocyte co-culture model, we observed a similar MT-I/-II response following in vitro injury. Intriguingly, scratch wound injury in pure astrocyte cultures resulted in no change in MT-I/-II expression. This suggests that MT induction was specifically elicited by neuronal injury. Based upon recent reports indicating that MT-I/-II are major neuroprotective proteins within the brain, our results provide further evidence that MT-I/-II plays an important role in the cellular response to neuronal injury.
Publisher: Wiley
Date: 18-09-2020
DOI: 10.1111/CODI.15311
Abstract: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were ided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7% routine NGT 5.2% reactive NGT 10.6% prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56–1.87, P = 0.932). In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion.
Publisher: Frontiers Media SA
Date: 17-06-2015
Publisher: Wiley
Date: 12-2001
DOI: 10.1046/J.0953-816X.2001.01825.X
Abstract: We investigated the possibility that estrogen and exercise interact in the hippoc us and regulate brain-derived neurotrophic factor (BDNF), a molecule increasingly recognized for its role in plasticity and neuron function. An important aspect of this study is to examine the effect of different time intervals between estrogen loss and estrogen replacement intervention. We demonstrate that in the intact female rat, physical activity increases hippoc al BDNF mRNA and protein levels. However, the exercise effect on BDNF up-regulation is reduced in the absence of estrogen, in a time-dependent manner. In addition, voluntary activity itself is stimulated by the presence of estrogen. In exercising animals, estrogen deprivation reduced voluntary activity levels, while estrogen replacement restored activity to normal levels. In sedentary animals, estrogen deprivation (ovariectomy) decreased baseline BDNF mRNA and protein, which were restored by estrogen replacement. Despite reduced activity levels in the ovariectomized condition, exercise increased BDNF mRNA levels in the hippoc us after short-term (3 weeks) estrogen deprivation. However, long-term estrogen-deprivation blunted the exercise effect. After 7 weeks of estrogen deprivation, exercise alone no longer affected either BDNF mRNA or protein levels. However, exercise in combination with long-term estrogen replacement increased BDNF protein above the effects of estrogen replacement alone. Interestingly, protein levels across all conditions correlated most closely with mRNA levels in the dentate gyrus, suggesting that expression of mRNA in this hippoc al region may be the major contributor to the hippoc al BDNF protein pool. The interaction of estrogen, physical activity and hippoc al BDNF is likely to be an important issue for maintenance of brain health, plasticity and general well-being, particularly in women.
Publisher: Public Library of Science (PLoS)
Date: 11-03-2011
Publisher: Frontiers Media SA
Date: 31-10-2014
Publisher: Elsevier BV
Date: 07-0011
Publisher: Public Library of Science (PLoS)
Date: 24-08-2017
Publisher: American Chemical Society (ACS)
Date: 09-07-2012
DOI: 10.1021/AC301156F
Abstract: Imaging of trace metal distribution in tissue sections by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) is typically performed using spatial resolutions of 30 μm(2) and above. Higher resolution imaging is desirable for many biological applications in order to approach the dimensions of a single cell. The limiting factor for increasing resolution is sensitivity, where signal-to-noise ratios are poor due to inherent background spectral interferences and reduced s le volume with decreasing laser beam diameter. Several prominent spectral interferences are present for a number of biologically relevant isotopes, including the (40)Ar(16)O(+) spectral interference on (56)Fe(+). We examined if H(2) as a reaction gas could improve the analytical performance of imaging experiments for a range of masses with spectral interferences. At low (<1 mL min(-1)) H(2) flow rates, greater spectral interference due to H(+) adducts was observed for (55)Mn, (57)Fe, and (59)Co. At higher flow rates of up to 3 mL H(2) per minute, the spectral interferences were reduced leading to improvement in limits of analysis for masses with O- and N-based polyatomic interferences. Enhanced sensitivity with the reaction cell allowed construction of high resolution (6 μm(2)) imaging of (56)Fe in the mouse brain that approached the dimensions of single cells.
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.
Publisher: Frontiers Media SA
Date: 23-06-2014
Publisher: Frontiers Media SA
Date: 25-06-2014
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.
Publisher: Public Library of Science (PLoS)
Date: 28-08-2013
Publisher: Wiley
Date: 06-2010
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.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8JA00324F
Abstract: We present a novel on-line isotope dilution analysis (IDA) approach for the quantification of isotopically enriched metal labels used in immunohistochemical assisted imaging mass spectrometry.
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.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.BBRC.2019.05.037
Abstract: Human amyloid-β
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
Publisher: Informa UK Limited
Date: 03-12-2018
DOI: 10.1080/02699052.2018.1552988
Abstract: This study sought to assess the potential efficacy of a novel class of metal chaperone on the outcomes in an animal model of a controlled cortical impact. This work was predicated on previous observations that this class of compound has exhibited neuroprotective potential in other models of aging and neurodegeneration. The study employed a controlled cortical impact traumatic brain injury in three month old mice with subsequent behavioral and cellular assessments to determine therapeutic efficacy. Cognitive (Y-maze) and motor assessments (Rotarod and Open Field) were employed to determine behavioral end points. Histological-based methods were utilized to assess neuronal integrity, astrocytosis, and lesion volume. We demonstrate here that acute post-injury treatment with PBT2 (Prana Biotechnology) is sufficient to maintain neuronal integrity (evidenced by decreased lesion area and increased numbers of neurons decreased astrocytosis was also present) and to normalize performance in cognitive testing (Y-maze). These effects occurred within days and were maintained for the entire duration of the study (26 days post-injury). These data support the further interrogation of the utility of metal chaperones for the treatment and/or prevention of the neuroanatomical, biochemical, and behavioral deficits that occur following brain injuries of different etiologies.
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.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2009
DOI: 10.1007/S11682-009-9067-2
Abstract: With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo. Molecular neuroimaging techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid, are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). (11)C-PiB PET has proven useful in the discrimination of dementias, showing significantly higher PiB retention in grey matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. (11)C-PiB PET also appears to be more accurate than FDG for the diagnosis of AD. Despite apparently underestimating the Aβ burden in the brain, (11)C-PiB PET is an optimal method to differentiate healthy controls from AD, matching histopathological reports in aging and dementia and reflecting the true regional density of Aβ plaques in cortical areas. High striatal Aβ deposition seems to be typical for carriers of familial forms of AD, whilst ApoE ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non- ε4 carriers. Characterization of the binding properties of PiB has shown that despite binding to other misfolded proteins in vitro, PiB is extremely selective for Aβ at the concentrations achieved during a PET scan. Aβ burden as assessed by PET does not correlate with measures of cognition or cognitive decline in AD. Approximately 30% of apparently healthy older people, and 50-60% of people with mild cognitive impairment, present with cortical (11)C-PiB retention. In these groups, Aβ burden does correlate with episodic memory and rate of memory decline. These observations suggest that Aβ deposition is not part of normal ageing, supporting the hypothesis that Αβ deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers are required not only to confirm this hypothesis, but also to better elucidate the role of Αβ deposition in the course of Alzheimer's disease.
Publisher: American Chemical Society (ACS)
Date: 22-12-2017
DOI: 10.1021/ACSCHEMNEURO.6B00362
Abstract: The metal ions of iron, copper, and zinc have long been associated with the aggregation of β-amyloid (Aβ) plaques in Alzheimer's disease an interaction that has been suggested to promote increased oxidative stress and neuronal dysfunction. We examined plaque metal load in the hippoc us of APP/PS1 mice using X-ray fluorescence microscopy to assess how the anatomical location of Aβ plaques was influenced by the metal content of surrounding tissue. Immunohistochemical staining of Aβ plaques colocalized with areas of increased X-ray scattering power in unstained tissue sections, allowing direct X-ray based-assessment of plaque metal levels in sections subjected to minimal chemical fixation. We identified and mapped 48 in idual plaques in four subregions of the hippoc us from four biological replicates. Iron, Cu, and Zn areal concentrations (ng cm
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.
Publisher: Wiley
Date: 08-07-2019
DOI: 10.1111/GBB.12594
Abstract: While Alzheimer's disease (AD) is traditionally associated with deficits in episodic memory, early changes in other cognitive domains, such as attention, have been gaining interest. In line with clinical observations, some animal models of AD have been shown to develop attentional deficits, but this is not consistent across all models. The APPswe/PS1ΔE9 (APP/PS1) mouse is one of the most commonly used AD models and attention has not yet been scrutinised in this model. We set out to assess attention using the 5-choice serial reaction time task (5CSRTT) early in the progression of cognitive symptoms in APP/PS1 mice, using clinically translatable touchscreen chambers. APP/PS1 mice showed no attentional changes across 5CSRTT training or any probes from 9 to 11 months of age. Interestingly, APP/PS1 mice showed increased impulsive and compulsive responding when task difficulty was high. This suggests that while the APP/PS1 mouse model may not be a good model of attentional changes in AD, it may be useful to study the early changes in impulsive and compulsive behaviour that have been identified in patient studies. As these changes have not previously been reported without attentional deficits in the clinic, the APP/PS1 mouse model may provide a unique opportunity to study these specific behavioural changes seen in AD, including their mechanistic underpinnings and therapeutic implications.
Publisher: Frontiers Media SA
Date: 13-08-2014
Publisher: Elsevier BV
Date: 03-2011
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4DT02969K
Abstract: [M(CO) 3 ] + (M = Tc/Re) complexes with tridentate ligands with a stilbene functional group bind to amyloid-β plaques associated with Alzheimer's Disease.
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.
Publisher: Mary Ann Liebert Inc
Date: 11-2000
Abstract: This study utilizes an in vitro model of localized physical injury to axons to examine the specific responses of neocortical neurons to trauma in isolation from glia cell types. The neuronal response to axotomy was closely linked with nerve cell maturity. Cultures grown for 14 days in vitro showed no accumulation of either neurofilaments or, the axonal sprouting marker, GAP43, within injured axons following injury. In older cultures (21 days in vitro), however, temporally distinct axonal changes were evident following transection of axonal bundles. At 12 h postinjury, these included extensive accumulation of neurofilaments into ring-like structures within the cut stumps and an increase in punctate GAP43 labelling throughout the damaged area. At 24 h postinjury, bulb-like accumulations of neurofilaments were also present within the transected axons. Finally at 3 days postinjury, distinct GAP43 and neurofilament immunolabeled axons, and GAP43 immunopositive growth cones, emanated from the cut stump. These results indicate that injured axons of mature neurons undergo a defined series of reactive changes, ultimately culminating in a sprouting response, which occur independently of the presence or effects of glial cell populations.
Publisher: Wiley
Date: 10-02-2013
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9JA00405J
Abstract: This work introduces a new method for immuno-mass spectrometry imaging via quadrupole-based laser ablation-inductively coupled plasma-mass spectrometry instruments that is matched to the abundance of elements in biological tissues.
Publisher: Wiley
Date: 04-12-2014
DOI: 10.1111/ACEL.12178
Publisher: Society for Neuroscience
Date: 25-02-2015
DOI: 10.1523/JNEUROSCI.3439-14.2015
Abstract: Elevation of both neuronal iron and nitric oxide (NO) in the substantia nigra are associated with Parkinson's disease (PD) pathogenesis. We reported previously that the Alzheimer-associated β-amyloid precursor protein (APP) facilitates neuronal iron export. Here we report markedly decreased APP expression in dopaminergic neurons of human PD nigra and that APP −/− mice develop iron-dependent nigral cell loss. Conversely, APP-overexpressing mice are protected in the MPTP PD model. NO suppresses APP translation in mouse MPTP models, explaining how elevated NO causes iron-dependent neurodegeneration in PD.
Publisher: Society for Neuroscience
Date: 03-02-2010
DOI: 10.1523/JNEUROSCI.5255-09.2010
Abstract: Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn 2+ levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6- to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippoc al proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (−46% p 0.01) the postsynaptic protein PSD95 (−37% p 0.01) the glutamate receptors AMPAR (−34% p 0.01), NMDAR2a (−64% p 0.001), and NMDAR2b (−49% p 0.05) the surrogate marker of neurogenesis doublecortin (−31% p 0.001) and elements of the BDNF pathway, pro-BDNF (−30% p 0.05) and TrkB (−22% p 0.01). In addition, there is a concomitant decrease in neuronal spine density (−6% p 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (−50% p 0.01) in healthy older humans (ages, 48–91 years r 2 = 0.47 p = 0.00019) and particularly in Alzheimer's disease (AD) (−36% p 0.0001). Thus, age-dependent loss of transsynaptic Zn 2+ movement leads to cognitive loss, and since extracellular β-amyloid is aggregated by and traps this pool of Zn 2+ , the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.
Publisher: Oxford University Press (OUP)
Date: 2010
DOI: 10.1039/C0MT00039F
Abstract: Three dimensional maps of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn) and phosphorous (P) in a 6-hydroxydopamine (6-OHDA) lesioned mouse brain were constructed employing a novel quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method known as elemental bio-imaging. The 3D maps were produced by ablating serial consecutive sections taken from the same animal. Each section was quantified against tissue standards resulting in a three dimensional map that represents the variation of trace element concentrations of the mouse brain in the area surrounding the substantia nigra (SN). Damage caused by the needle or the toxin did not alter the distribution of Zn, and Cu but significantly altered Fe in and around the SN and both Mn and Fe around the needle track. A 20% increase in nigral Fe concentration was observed within the lesioned hemisphere. This technique clearly shows the natural heterogeneous distributions of these elements throughout the brain and the perturbations that occur following trauma or intoxication. The method may applied to three-dimensional modelling of trace elements in a wide range of tissue s les.
Publisher: MDPI AG
Date: 21-01-2019
DOI: 10.3390/NU11010206
Abstract: Acrodermatitis enteropathica (AE) is a rare disease characterised by a failure in intestinal zinc absorption, which results in a host of symptoms that can ultimately lead to death if left untreated. Current clinical treatment involves life-long high-dose zinc supplements, which can introduce complications for overall nutrient balance in the body. Previous studies have therefore explored the pharmacological treatment of AE utilising metal ionophore/transport compounds in an animal model of the disease (conditional knockout (KO) of the zinc transporter, Zip4), with the perspective of finding an alternative to zinc supplementation. In this study we have assessed the utility of a different class of zinc ionophore compound (zinc diethyl bis(N4-methylthiosemicarbazone), Zn-DTSM Collaborative Medicinal Development, Sausalito, CA, USA) to the one we have previously described (clioquinol), to determine whether it is effective at preventing the stereotypical weight loss present in the animal model of disease. We first utilised an in vitro assay to assess the ionophore capacity of the compound, and then assessed the effect of the compound in three in vivo animal studies (in 1.5-month-old mice at 30 mg/kg/day, and in 5-month old mice at 3 mg/kg/day and 30 mg/kg/day). Our data demonstrate that Zn-DTSM has a pronounced effect on preventing weight loss when administered daily at 30 mg/kg/day this was apparent in the absence of any added exogenous zinc. This compound had little overall effect on zinc content in various tissues that were assessed, although further characterisation is required to more fully explore the cellular changes underlying the physiological benefit of this compound. These data suggest that Zn-DTSM, or similar compounds, should be further explored as potential therapeutic options for the long-term treatment of AE.
Publisher: Public Library of Science (PLoS)
Date: 10-04-2019
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.NEUROBIOLAGING.2013.10.089
Abstract: A neuro-inflammatory response has been implicated in human patients and animal models of Alzheimer's disease (AD). Type-1 interferons are pleiotropic cytokines involved in the initiation and regulation of the pro-inflammatory response however, their role in AD is unknown. This study investigated the contribution of type-1 IFN signaling in the neuro-inflammatory response to amyloid-beta (Aβ) in vitro and in the APP/PS1 transgenic mouse model of AD. Enzyme-linked immunosorbent assay confirmed a 2-fold increase in IFNα in APP/PS1 brains compared with control brains. Quantitative polymerase chain reaction also identified increased IFNα and IFNβ expression in human pre-frontal cortex from AD patients. In vitro studies in primary neurons demonstrated Aβ-induced type-1 IFN expression preceded that of other classical pro-inflammatory cytokines, IL1-β, and IL-6. Significantly, ablation of type-1 interferon-α receptor 1 expression in BE(2)M17 neuroblastoma cells and primary neurons afforded protection against Aβ-induced toxicity. This study supports a role for type-1 interferons in the pro-inflammatory response and neuronal cell death in AD and suggests that blocking type-1 interferon-α receptor 1 maybe a therapeutic target to limit the disease progression.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.EXGER.2010.10.001
Abstract: While chronic or severe stress generally has negative consequences in the brain, moderate stress has been shown to facilitate learning in young animals. It is unknown if stress facilitates or impairs learning in an aged animal. In this study, the effect of mild stress on learning and task retention (1 week later) was assessed in young and aged mice. In addition, because exercise can counteract negative effects of stress and facilitate learning, the effect of 1 week of voluntary exercise on task retention was assessed. Regulation of the learning/memory related genes BDNF exon VI, synapsin, MAPK, and CRFR1 were also examined in the hippoc us using real-time PCR. Results of this study demonstrate that mild stress 24h prior to the learning test improved performance in aged, but not young animals. However, exercise for 1 week between tests improved the performance of both groups of animals in the retention task. In aged, but not young animals, all four genes increased significantly after exercise. Thus, in aged animals mild stress facilitates learning and the retention of this task is improved by voluntary exercise.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Springer Science and Business Media LLC
Date: 10-07-2014
Publisher: American Chemical Society (ACS)
Date: 19-06-2018
DOI: 10.1021/ACSCHEMNEURO.8B00161
Abstract: Alzheimer's disease (AD) is the leading cause of dementia worldwide accounting for around 70% of all cases. There is currently no treatment for AD beyond symptom management and attempts at developing disease-modifying therapies have yielded very little. These strategies have traditionally targeted the peptide Aβ, which is thought to drive pathology. However, the lack of clinical translation of these Aβ-centric strategies underscores the need for erse treatment strategies targeting other aspects of the disease. Metal dyshomeostasis is a common feature of several neurodegenerative diseases such as AD, Parkinson's disease, and frontotemporal dementia, and manipulation of metal homeostasis has been explored as a potential therapeutic avenue for these diseases. The copper ionophore glyoxalbis-[N4-methylthiosemicarbazonato]Cu(II) (Cu
Publisher: Springer Science and Business Media LLC
Date: 04-2002
DOI: 10.1007/S00401-001-0476-6
Abstract: We have investigated the effects of the deposition of insoluble beta-amyloid plaques on dendritic morphology within the neocortex. Labelling for beta-amyloid identified three morphologically distinct plaque types present both within the brains of preclinical Alzheimer's disease (AD) and end-stage AD cases. In both preclinical and end-stage AD, the percentage area occupied by diffuse plaques contained a greater density of labelling for microtubule-associated protein-2 (MAP2) relative to the surrounding neuropil (case type, ratio of MAP2 labelling in plaque to MAP2 labelling in surrounding neuropil +/- SEM: preclinical, 1.27+/-0.04 end-stage, 1.32+/-0.05). In contrast, there was a greater density of MAP2-labelled processes surrounding dense-cored plaques compared to that found within the plaque area (preclinical, 0.73+/-0.05 end-stage, 0.62+/-0.07). Fibrillar plaques demonstrated a transition from the early to late stages of AD, with a substantial decrease in the density of MAP2 labelling within the plaque area in end-stage AD cases relative to preclinical AD cases (preclinical, 1.01+/-0.1 end-stage, 0.72+/-0.05). The morphology of dendrites associated with dense-core or fibrillar plaques suggest physical disruption of the neuropil by beta-amyloid plaque formation. These data demonstrate that plaque isoforms differentially affect dendritic morphology in both the early and late stages of AD, with progression to clinical AD associated with evolving dendritic damage localised to fibrillar and dense-core plaques.
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.
Publisher: Oxford University Press (OUP)
Date: 18-11-2019
DOI: 10.1039/C9MT00196D
Abstract: Down syndrome (DS) is a common intellectual disability, with an incidence of 1 in 700 and is caused by trisomy 21. People with DS develop Alzheimer's disease (AD)-like neuropathology by the age of 40. As metal ion dyshomeostasis (particularly zinc, iron and copper) is one of the characteristics of AD and is believed to be involved in the pathogenesis of disease, we reasoned that it may also be altered in DS. Thus, we used inductively coupled plasma mass spectrometry to examine metal levels in post-mortem brain tissue from DS in iduals with concomitant AD pathology. Size exclusion-ICPMS was also utilised to characterise the metalloproteome in these cases. We report here for the first time that iron levels were higher in a number of regions in the DS brain, including the hippoc us (40%), frontal cortex (100%) and temporal cortex (34%), compared to controls. Zinc and copper were also elevated (both 29%) in the DS frontal cortex, but zinc was decreased (23%) in the DS temporal cortex. Other elements were also examined, a number of which also showed disease-specific changes. The metalloproteomic profile in the DS brain was also different to that in the controls. These data suggest that metals and metal:protein interactions are dysregulated in the DS brain which, given the known role of metals in neurodegeneration and AD, is likely to contribute to the pathogenesis of disease. Interrogation of the underlying cellular mechanisms and consequences of this failure in metal ion homeostasis, and the specific contributions of the in idual DS and AD phenotypes to these changes, should be explored.
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.NEUROBIOLAGING.2004.05.006
Abstract: Voluntary exercise increases hippoc al brain-derived neurotrophic factor (BDNF) expression in young animals. In this investigation we examined the induction of BDNF protein in the hippoc us of young (2 months), late middle-aged (15 months) and old (24 months) animals over 4 weeks of exercise. Average running distances decreased with age, with the old animals also maintaining a constant level of activity over time, whereas the other groups tended to increase their average running distance. All animals demonstrated a biphasic profile of BDNF protein induction, with a significant (P<0.05) increase after 1 week of exercise followed by a decrease to near sedentary levels at 2 weeks. After this, BDNF protein levels increased significantly (P<0.05), as compared to baseline, primarily only in the young animals. In whole hippoc al homogenates, only particular BDNF mRNA exons were significantly (P<0.05) changed as a result of exercise, with the largest induction occurring in young animals. BDNF protein induction may, therefore, not be directly correlated with significant mRNA changes. Exercise may represent a therapeutic tool for disorders which involve a decrease in BDNF.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-01-2009
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.
Location: Australia
No related grants have been discovered for Paul Adlard.