-
[show abstract]
[hide abstract]
ABSTRACT: Braak's proposal that, in patients with Parkinson's disease, Lewy bodies and neurites progressively invade the brain through regions connected to autonomic and olfactory centers remains contentious. Confounding factors include the lack of an in vivo marker to examine the progression of Lewy pathology, the retrospective nature or absence of clinical information for many cross-sectional pathological datasets, and for those with limited disease (clinically or neuropathologically), the absence of information concerning additional conditions. Despite these data limitations at this time, the brain pathology for most patients with typical Parkinson's disease can be predicted using Braak's scheme. What this tells us about the pathogenesis of Parkinson's disease will be explored in this review.
Expert Review of Neurotherapeutics 06/2012; 12(6):673-86.
-
[show abstract]
[hide abstract]
ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia, and amyloid-β (Aβ) plaques and tau-containing tangles are its histopathological hallmark lesions. These do not occur at random; rather, the neurodegenerative process is stereotyped in that it is initiated in the entorhinal cortex and hippocampal formation. Interestingly, it is the latter brain area where the calcium-sensing enzyme hippocalcin is highly expressed. Because calcium deregulation is a well-established pathomechanism in AD, we aimed to address the putative role of hippocalcin in human AD brain and transgenic mouse models. We found that hippocalcin levels are increased in human AD brain and in Aβ plaque-forming APP23 transgenic mice compared to controls. To determine the role of hippocalcin in Aβ toxicity, we treated primary cultures derived from hippocalcin knockout (HC KO) mice with Aβ and found them to be more susceptible to Aβ toxicity than controls. Likewise, treatment with either thapsigargin or ionomycin, both known to deregulate intracellular calcium levels, caused an increased toxicity in hippocampal neurons from HC KO mice compared to wild-type. We found further that mitochondrial complex I activity increased from 3 to 6months in hippocampal mitochondria from wild-type and HC KO mice, but that the latter exhibited a significantly stronger aging phenotype than wild-type. Aβ treatment induced significant toxicity on hippocampal mitochondria from HC KO mice already at 3months of age, while wild-type mitochondria were spared. Our data suggest that hippocalcin has a neuroprotective role in AD, presenting it as a putative biomarker.
Biochimica et Biophysica Acta 04/2012; 1822(8):1247-57. · 4.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause autosomal dominant
familial Alzheimer’s disease (AD). PSEN1 and PSEN2 are essential components of the γ-secretase complex, which cleaves APP
to affect Aβ processing. Disruptions in Aβ processing have been hypothesised to be the major cause of AD (the amyloid cascade
hypothesis). These genetic cases exhibit all the classic hallmark pathologies of AD including neuritic plaques, neurofibrillary
tangles (NFT), tissue atrophy, neuronal loss and inflammation, often in significantly enhanced quantities. In particular,
these cases have average greater hippocampal atrophy and NFT, more significant cortical Aβ42 plaque deposition and more substantial
inflammation. Enhanced cerebral Aβ40 angiopathy is a feature of many cases, but particularly those with APP mutations where
it can be the dominant pathology. Additional frontotemporal neuronal loss in association with increased tau pathology appears
unique to PSEN mutations, with mutations in exons 8 and 9 having enlarged cotton wool plaques throughout their cortex. The
mechanisms driving these pathological differences in AD are discussed.
Acta Neuropathologica 04/2012; 118(1):37-52. · 9.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause autosomal dominant familial Alzheimer's disease (AD). PSEN1 and PSEN2 are essential components of the gamma-secretase complex, which cleaves APP to affect Abeta processing. Disruptions in Abeta processing have been hypothesised to be the major cause of AD (the amyloid cascade hypothesis). These genetic cases exhibit all the classic hallmark pathologies of AD including neuritic plaques, neurofibrillary tangles (NFT), tissue atrophy, neuronal loss and inflammation, often in significantly enhanced quantities. In particular, these cases have average greater hippocampal atrophy and NFT, more significant cortical Abeta42 plaque deposition and more substantial inflammation. Enhanced cerebral Abeta40 angiopathy is a feature of many cases, but particularly those with APP mutations where it can be the dominant pathology. Additional frontotemporal neuronal loss in association with increased tau pathology appears unique to PSEN mutations, with mutations in exons 8 and 9 having enlarged cotton wool plaques throughout their cortex. The mechanisms driving these pathological differences in AD are discussed.
Acta Neuropathologica 04/2009; 118(1):37-52. · 9.32 Impact Factor
-
[show abstract]
[hide abstract]
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.
Acta Neuropathologica 11/2008; 117(1):19-29. · 9.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Alzheimer's disease (AD) is characterized by Abeta peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Abeta plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting beta-amyloid peptide 1-42 (Abeta42) into brains of P301L tau mutant mice. In cell culture, Abeta42 induces filamentous tau aggregates. To understand which processes are disrupted by Abeta42 in the presence of tau aggregates, we applied comparative proteomics to Abeta42-treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Abeta42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Abeta42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Abeta42-mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.
PROTEOMICS 01/2007; 6(24):6566-77. · 4.51 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Alzheimer's disease (AD) is characterized by Aβ peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Aβ plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting β-amyloid peptide 1-42 (Aβ42) into brains of P301L tau mutant mice. In cell culture, Aβ42 induces filamentous tau aggregates. To understand which processes are disrupted by Aβ42 in the presence of tau aggregates, we applied comparative proteomics to Aβ42-treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Aβ42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Aβ42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Aβ42-mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.
Proteomics 11/2006; 6(24):6566 - 6577. · 4.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: SUMMARY1. Of the neurodegenerative diseases that cause dementia, Alzheimer’s disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology.2. The senile plaques of AD consist primarily of complexes of the β-amyloid protein. This protein is central to the pathogenesis of the disease.3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. β-Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin.4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti-inflammatory drugs. Longitudinal studies have shown that the consumption of anti-inflammatory medications reduces the risk of AD only in younger patients (< 75 years).5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non-steroidal anti-inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD.6. Cyclo-oxygenase 2 enzyme is constitutively expressed in neurons and is up-regulated in degenerative brain regions in AD. Non-steroidal anti-inflammatory drugs may reduce this expression.7. Platelets are a source of β-amyloid and increased platelet activation and increased circulating β-amyloid have been identified in AD. Anti-platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences.8. Increased levels of luminal β-amyloid permeabilizes the blood–brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity. Anti-inflammatory medications may alleviate these problems.
Clinical and Experimental Pharmacology and Physiology 12/2003; 27(1‐2):1 - 8. · 1.85 Impact Factor
-
ECU Publications.
