ORCID Profile
0000-0002-4246-7624
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Publisher: Wiley
Date: 09-11-2020
DOI: 10.1111/JNC.15214
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BRAINRESBULL.2009.08.004
Abstract: There has been growing interest in the axon as the initial focus of pathological change in a number of neurodegenerative diseases of the central nervous system. This review concentrates on three major neurodegenerative conditions--amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer's disease--with emphasis on key cellular changes that may underlie early axonal dysfunction and pathology and, potentially, the degeneration of neurons. In particular, this review will address recent data that indicate that the main pathological stimuli for these conditions, though often not definitively determined, result in an initial perturbation of the axon and its cytoskeleton, which then results in slow neuronal degeneration and loss of connectivity. The identification of a degenerative process initiated in the axon may provide new therapeutic targets for early intervention to inhibit the grim outcomes related to the progression of these diseases.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.NBD.2005.11.010
Abstract: Apoptotic-like changes in the neocortex of control, pathologically aged and Alzheimer's disease (AD) cases were investigated. There was no increase in labeling or change in localization of labeling that distinguished between these cases for active caspase-3, -8, -9, Bax, Bcl-2 or TRADD. Bax, Bcl-2 and TRADD mRNA levels also differed little between case types, although there were small but significant decreases in Bax mRNA levels in AD compared to control cases and Bcl-2 mRNA in AD cases compared to pathologically aged and control cases. There was no difference in the percentage of apoptotic-like nuclei between these cases, except for a small but significant decrease in the inferior temporal gyrus of AD cases relative to controls. Nuclei observed within or adjacent to beta-amyloid plaques were rarely abnormal, and neurons bearing neurofibrillary tangles (NFTs) did not have abnormal nuclei. Apoptosis may not play a major role in the pathogenesis of neuronal degeneration of AD.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Public Library of Science (PLoS)
Date: 11-08-2010
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.NEUROBIOLAGING.2009.04.004
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating disorder involving loss of movement due to degeneration of motor neurons. Studies suggest that in ALS axonal dysfunction precedes the death of motor neurons. Pathologically, ALS is characterized by neurofilamentous swellings (spheroids) within the axons of motor neurons. However, the causes of this axonopathy and possible resulting axonal dysfunction are not known. Using a novel model of cultured mouse motor neurons, we have determined that these neurons are susceptible to proximal axonopathy, which is related to the glial environment. This axonopathy showed remarkable similarity, both morphologically and neurochemically, to spheroids that develop over months in SOD1(G93A) transgenic mice. Focal ubiquitination, as well as perturbations of neurofilaments and microtubules, occurred in the axonal spheroid-like swellings in vitro, and visualization of mitochondrial dynamics demonstrated that axonopathy resulted in impaired axonal transport. These data provide strong evidence for the involvement of non-neuronal cells in axonal dysfunction in ALS. This cell culture model may be of benefit for the development of therapeutic interventions directed at axonal preservation.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2006
DOI: 10.1007/S00401-006-0107-3
Abstract: Cytochrome c has a well-established role in electron transfer and as a mediator of apoptotic cell death. The cortical and intracellular localisation of cytochrome c immunoreactivity was examined in Alzheimer's disease and control cases. No differences in the cortical labelling pattern or the density of cytochrome c-positive cells in neocortical layer V were present between control and Alzheimer's disease cases. Punctate cytochrome c labelling was present in a subset of neocortical neurons, including clusters of intensely labelled pyramidal neurons that were not specifically associated with beta-amyloid plaques. With respect to Alzheimer's disease associated pathology, only 6.7 +/- 1.4% of neurons showing neurofibrillary tangle formation demonstrated punctate cytochrome c immunoreactivity. These results suggest that cytochrome c may label a subset of pyramidal neurons that is susceptible, yet relatively resistant, to Alzheimer's disease pathology. A low percentage of neurofilament triplet protein medium, tau and chromogranin A labelled dystrophic neurites were also cytochrome c-positive. There was also a trend towards an increase in the percentage of cytochrome c immunoreactive dystrophic neurites in pathologically aged control cases compared to Alzheimer's disease cases, suggesting that cytochrome c may be an early and transient epitope within dystrophic neurites. In contrast to the punctate cytochrome c labelling observed in cortical cells, cytoplasmic cytochrome c labelling was observed within dystrophic neurites. Although cytochrome c release is indicative of the activation of the intrinsic apoptotic pathway, cytoplasmic cytochrome c may also indicate mitochondrial damage or dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2008
DOI: 10.1007/S00401-008-0458-Z
Abstract: Most cases of Alzheimer's disease (AD) are sporadic in nature, although rarer familial AD (FAD) cases have provided important insights into major pathological disease mechanisms. Mutations in the presenilin 1 gene (PS1) are responsible for the majority of FAD cases, causing an earlier age of onset and more rapid progression to end-stage disease than seen in sporadic AD. We have investigated the cytoskeletal alterations in neuritic AD pathology in a cohort of FAD cases in comparison to sporadic AD and pathologically aged cases. Tau-immunoreactive neurofibrillary tangle (NFT) loads were similar between PS1 FAD and sporadic AD cases. Similarly, plaque loads, both beta-amyloid (Abeta) and thioflavine S, in PS1 FAD and sporadic AD cases were not significantly different however, in pathologically aged cases, they were significantly lower than those in PS1 cases, but were not different from sporadic AD cases. The 'cotton wool' plaque characteristic of PS1 cases did not demonstrate a high density of dystrophic neurites compared to other Abeta plaque types, but did demonstrate a localised mass effect on the neuropil. Despite minimal differences in plaque and NFT loads, immunolabelling demonstrated clear phenotypic differences in the NFTs and dystrophic neurites in PS1 FAD cases. Presenilin-1 cases exhibited significantly (P < 0.05) more tau-positive NFTs that were immunolabelled by the antibody SMI312 (anti-phosphorylated NF protein and phosphorylated tau) than sporadic AD cases. Presenilin-1 cases also exhibited numerous ring-like NF-positive and elongated tau-labelled dystrophic neurites, whereas these dystrophic neurite types were only abundant at the very early (pathologically aged cases) or very late stages of sporadic AD progression, respectively. These differences in cytoskeletal pathology in PS1 cases suggest an accelerated rate of neuritic pathology development, potentially due to mutant PS1 influencing multiple pathogenic pathways.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.NEUROBIOLAGING.2015.07.003
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with the loss of cognitive function. Neurofilament (NF) triplet proteins, the major structural (intermediate filament) proteins of neurons, are expressed in a subset of pyramidal cells that show a high degree of vulnerability to degeneration in AD. Alterations in the NF triplet proteins in amyloid-beta (Aβ) plaque-associated dystrophic neurites (DNs) represent the first cytoskeletal aberration to occur in the neocortex in the earliest stages of AD. We generated transgenic APP/PS1 (APPswe/PSEN1dE9) mice on the neurofilament light knockout (NFL KO) background to explore the role of NFL deletion in the context of DN formation, synaptic changes, and other neuropathologic features. Our analysis demonstrated that NFL deficiency significantly increased neocortical DN pathology, Aβ deposition, synapse vulnerability, and microgliosis in APP/PS1 mice. Thus, NFs may have a role in protecting neurites from dystrophy and in regulating cellular pathways related to the generation of Aβ plaques.
Publisher: Mary Ann Liebert Inc
Date: 06-2019
Abstract: Traumatic brain injury (TBI) has been identified as a risk factor for Alzheimer's disease (AD). However, how such neural damage contributes to AD pathology remains unclear specifically, the relationship between the timing of a TBI relative to aging and the onset of AD pathology is not known. In this study, we have examined the effect of TBI on subsequent beta-amyloid (Aβ) deposition in APP/PS1 (APP
Publisher: Springer Science and Business Media LLC
Date: 2007
DOI: 10.2165/00002512-200724020-00003
Abstract: The pathological hallmarks of Alzheimer's disease (AD) include beta-amyloid (Abeta) plaques, dystrophic neurites and neurofibrillary pathology, which eventually result in the degeneration of neurons and subsequent dementia. In 1999, international interest in a new therapeutic approach to the treatment of AD was ignited following transgenic mouse studies that indicated that it might be possible to immunise against the pathological alterations in Abeta that lead to aggregation of this protein in the brain. A subsequent phase I human trial for safety, tolerability and immunogenicity using an active immunisation strategy against Abeta had a positive outcome. However, phase IIA human trials involving active immunisation were halted following the diagnosis of aseptic meningoencephalitis in 6% of immunised subjects. Research into immunisation strategies involving transgenic AD mouse models has subsequently been refocused to determine the mechanisms by which plaque clearance and reduced memory deficits are attained, and to establish safer therapeutic approaches that may reduce potentially harmful brain inflammation. The vigour of international research on immunotherapy for AD provides significant hope for a strong therapeutic lead for the escalating number of in iduals who will develop this otherwise incurable condition.
Publisher: Springer Science and Business Media LLC
Date: 05-2004
DOI: 10.1007/S00018-004-4026-Y
Abstract: Olfactory ensheathing cells (OECs) represent an exciting possibility for promoting axonal regeneration within the injured spinal cord. A number of studies have indicated the ability of these cells to promote significant reactive sprouting of injured axons within the injured spinal cord, and in some cases restoration of functional abilities. However, the cellular and/or molecular mechanisms OECs use to achieve this are unclear. To investigate such mechanisms, we report for the first time the ability of OECs to promote post-injury neurite sprouting in an in vitro model of axonal injury. Using this model, we were able to differentiate between the direct and indirect mechanisms underlying the ability of OECs to promote neuronal recovery from injury. We noted that OECs appeared to act as a physical substrate for the growth of post-injury neurite sprouts. We also found that while post-injury sprouting was promoted most when OECs were allowed to directly contact injured neurons, physical separation using tissue culture inserts (1 mm pore size, permeable to diffusible factors but not cells) did not completely block the promoting properties of OECs, suggesting that they also secrete soluble factors which aid post-injury neurite sprouting. Furthermore, this in vitro model allowed direct observation of the cellular interactions between OECs and sprouting neurites using live-cell-imaging techniques. In summary, we found that OECs separately promote neurite sprouting by providing a physical substrate for growth and through the expression of soluble factors. Our findings provide new insight into the ability of OECs to promote axonal regeneration, and also indicate potential targets for manipulation of these cells to enhance their restorative ability.
Publisher: Frontiers Media SA
Date: 03-04-2019
Publisher: Springer Science and Business Media LLC
Date: 25-04-2018
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.EXPNEUROL.2015.02.034
Abstract: Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aβ) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aβ plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aβ plaques but focal injury had no statistically significant (p>0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p 0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice p 0.05). There was no significant effect of genotype on this response (p>0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aβ plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aβ plaque pathology that causes synaptic degeneration.
Publisher: Bentham Science Publishers Ltd.
Date: 12-02-2016
DOI: 10.2174/1567205013666151218150322
Abstract: The prospects for effectively treating well-established dementia, such as Alzheimer's disease (AD), are slim, due to the destruction of key brain pathways that underlie higher cognitive function. There has been a substantial shift in the field towards detecting conditions such as AD in their earliest stages, which would allow preventative or therapeutic approaches to substantially reduce risk and/or slow the progression of disease. AD is characterized by hallmark pathological changes such as extracellular Aβ plaques and intracellular neurofibrillary pathology, which selectively affect specific subclasses of neurons and brain circuits. Current evidence indicates that Aβ plaques begin to form many years before overt dementia, a gradual and progressive pathology which offers a potential target for early intervention. Early Aβ changes in the brain result in localized damage to dendrites, axonal processes and synapses, to which excitatory synapses and the processes of projection neurons are highly vulnerable. Aβ pathology is replicated in a range of transgenic models overexpressing mutant human familial AD genes (e.g. APP and presenilin 1). Studying the development of aberrant regenerative and degenerative changes in neuritic processes associated with Aβ plaques may represent the best opportunity to understand the relationship between the pathological hallmarks of AD and neuronal damage, and to develop early interventions to prevent, slow down or mitigate against Aβ pathology and/or the neuronal alterations that leads to cognitive impairment.
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: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1007/BF03033772
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.EXPNEUROL.2015.09.019
Abstract: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that results in motor dysfunction and death, generally from respiratory failure. 90% of ALS cases are sporadic with no known cause. Familial cases have been linked with mutations in several disparate classes of genes, including those involved in DNA/RNA metabolism, protein misfolding, oxidative stress and the cytoskeleton, leading to the proposition that ALS could be a multi-factorial disease. However, alterations in excitability have been reported in all types of ALS cases, and may be a common disease mechanism predisposing neurons to degeneration. Excitotoxicity has long been suspected as a mediator in the disease process, and may arise from changes in synaptic inputs, or alterations in the excitability of the neurons being stimulated. Although the glutamatergic system is widely recognised as a therapeutic avenue with the potential to extend lifespan and delay disease onset, the causes of altered excitability in ALS are currently unclear and warrant further investigation. This article reviews current evidence of alterations to excitatory and inhibitory signalling in the cortex and spinal cord, and in the intrinsic excitability of motor neurons, in ALS.
Publisher: Mary Ann Liebert Inc
Date: 03-2020
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NEUROBIOLAGING.2016.05.003
Abstract: There is increasing evidence that epigenetic alterations may play a role in Alzheimer's disease (AD) yet, there is little information regarding epigenetic modifications in specific cell types. We assessed DNA methylation (5-methylcytosine [5mC]) and hydroxymethylation (5-hydroxymethylcytosine [5hmC]) marks specifically in neuronal and glial cell types in the inferior temporal gyrus of human AD cases and age-matched controls. Interestingly, neurofilament (NF)-labeled pyramidal neurons that are vulnerable to AD pathology are deficient in extranuclear 5mC in AD cases compared with controls. We also found that fewer astrocytes exhibited nuclear 5mC and 5hmC marks in AD cases compared with controls. However, there were no alterations in 5mC and 5hmC in disease-resistant calretinin interneurons or microglia in AD, and there was no alteration in the density of 5mC- or 5hmC-labeled nuclei in near-plaque versus plaque-free regions in late-AD cases. 5mC and 5hmC were present in a high proportion of neurofibrillary tangles, suggesting no loss of DNA methylation marks in tangle bearing neurons. We provide evidence that epigenetic dysregulation may be occurring in astrocytes and NF-positive pyramidal neurons in AD.
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2021
DOI: 10.1101/2021.11.11.467877
Abstract: Neurons live for the lifespan of the in idual and underlie our ability for lifelong learning and memory. However, aging alters neuron morphology and function resulting in age-related cognitive decline. It is well established that epigenetic alterations are essential for learning and memory, yet few neuron-specific genome-wide epigenetic maps exist into old age. Comprehensive mapping of H3K4me3 and H3K27ac in mouse neurons across lifespan revealed plastic H3K4me3 marking that differentiates neuronal age linked to known characteristics of cellular and neuronal aging. We determined that neurons in old age recapitulate the H3K27ac enrichment at promoters, enhancers and super enhancers from young adult neurons, likely representing a re-activation of pathways to maintain neuronal output. Finally, this study identified new characteristics of neuronal aging, including altered rDNA regulation and epigenetic regulatory mechanisms. Collectively, these findings indicate a key role for epigenetic regulation in neurons, that is inextricably linked with aging.
No related organisations have been discovered for Adele Woodhouse.
Start Date: 2016
End Date: 2016
Funder: University of Tasmania
View Funded ActivityStart Date: 2015
End Date: 2015
Funder: The Mason Foundation
View Funded Activity