Cortical α-synuclein load is associated with amyloid-β plaque burden in a subset of Parkinson’s disease patients. Acta Neuropathol

Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
Acta Neuropathologica (Impact Factor: 10.76). 05/2008; 115(4):417-25. DOI: 10.1007/s00401-007-0336-0
Source: PubMed


Amyloid-beta (Abeta) peptide pathology in Alzheimer's disease (AD) comprises extracellular plaques and cerebral amyloid angiopathy (CAA). In Parkinson's disease (PD), alpha-synuclein forms intraneuronal Lewy bodies (LBs), and cortical LBs are thought to play a major role in cognitive decline designated as PD with dementia. As there is increasing evidence that Abeta may also promote alpha-synuclein fibrillization, we assessed the relationship between LB pathology and Abeta deposition in 40 cases of PD and 20 age-matched controls. In five cortical areas, we established the severity of Abeta plaque load using an approach similar to that recommended by CERAD in AD. LB densities were determined using a morphometric approach. CAA was graded using previously described scales. The APOE genotype was established in 38 PD and 19 control cases. We have found that the overall Abeta plaque burden and, in particular, the diffuse plaque load shows a statistically significant 'large' correlation with the overall cortical LB burden. The strength of this correlation further increases in PD cases (about 50% of the cases) with moderate to high Abeta plaque load. The APOE epsilon4 allele is over-represented in this subgroup. Our data indicate a strong association between pathologically identifiable Abeta plaque burden and alpha-synuclein load in cerebral cortex and provide indirect evidence that Abeta pathology is likely to be an important factor contributing to cognitive decline in a subgroup of PD patients.

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    • "Alzheimer-type neurofibrillary tangle pathology was assessed using Braak and Braak staging (Braak et al., 2006). The extent and severity of CAA was determined based on a 4-tier grading system (Lashley et al., 2008; Olichney et al., 1996), described in Supplementary Information. Quantitation of the immunohistochemical stains was undertaken to assess any deep white matter changes in the occipital and parietal regions. "
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    ABSTRACT: Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD.
    Neurobiology of aging 09/2015; DOI:10.1016/j.neurobiolaging.2015.08.026 · 5.01 Impact Factor
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    • "Longitudinal analysis of motor and cognitive ratings may be more appropriate and could reveal whether CSF levels of Ab 1e42 , a-syn, and tau predict disease progression. Alternatively, the correlation between CSF Ab 1e42 and a-syn suggests that the poorer prognosis found at autopsy in those PD patients who had abnormal Ab compared with those who did not (Kotzbauer et al., 2012) could reflect a higher a-syn burden in the brain rather than an additive effect of Ab as suggested by previously observed correlations between Lewy body and Ab plaque densities (Lashley et al., 2008; Pletnikova et al., 2005). Further studies quantifying abnormal accumulation of both of these proteins could be revealing. "
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    ABSTRACT: Accumulation of misfolded α-synuclein (α-syn) protein in Lewy bodies and neurites is the cardinal pathologic feature of Parkinson disease (PD), but abnormal deposition of other proteins may also play a role. Cerebrospinal fluid (CSF) levels of proteins known to accumulate in PD may provide insight into disease-associated changes in protein metabolism and their relationship to disease progression. We measured CSF α-syn, amyloid β1-42 (Aβ1-42), and tau from 77 nondemented PD and 30 control participants. CSF α-syn and Aβ1-42 were significantly lower in PD compared with controls. In contrast with increased CSF tau in Alzheimer disease, CSF tau did not significantly differ between PD and controls. CSF protein levels did not significantly correlate with ratings of motor function or performance on neuropsychological testing. As expected, CSF Aβ1-42 inversely correlated with [(11)C]-Pittsburgh compound B (PiB) mean cortical binding potential, with PiB(+) PD participants having lower CSF Aβ1-42 compared with PiB(-) PD participants. Furthermore, CSF α-syn positively correlated with Aβ1-42 in PD participants but not in controls, suggesting a pathophysiologic connection between the metabolisms of these proteins in PD.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.043 · 5.01 Impact Factor
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    • "nd burden are clearly increased in 2 / 3 of PD with dementia patients or DLB cases using the Pittsburgh compound B positron emission tomo - graphy ( PIB - PET ) imaging technique ( Gomperts et al . 2008 ; Burack et al . 2010 ) . In PD alone , 50% of cases manifest high correlation between cortical Synuclein load and diffuse amyloid plaque burden ( Lashley et al . 2008 ) . Elevated brain levels of Ab 1 – 42 in familial Lewy body disease ( LBD ) ( Kaneko et al . 2007 ) further illustrates the concept that a - synuclein and Ab accumulations might be inter - connected . There is even cross - association between a - synuclein burden and NFT load in familial PD ( Duda et al . 2002 ) . It is clear that at t"
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    ABSTRACT: J. Neurochem. (2012) 120, 350–370. The study of neurodegenerative disorders has had a major impact on our understanding of more fundamental mechanisms underlying neurobiology. Breakthroughs in the genetics of Alzheimer’s (AD) and Parkinson’s diseases (PD) has resulted in new knowledge in the areas of axonal transport, energy metabolism, protein trafficking/clearance and synaptic physiology. The major neurodegenerative diseases have in common a regional or network pathology associated with abnormal protein accumulation(s) and various degrees of motor or cognitive decline. In AD, β-amyloids are deposited in extracellular diffuse and compacted plaques as well as intracellularly. There is a major contribution to the disease by the co-existence of an intraneuronal tauopathy. Additionally, PD-like Lewy Bodies (LBs) bearing aggregated α-synuclein is present in 40–60% of all AD cases, especially involving amygdala. Amyloid deposits can be degraded or cleared by several mechanisms, including immune-mediated and transcytosis across the blood–brain barrier. Another avenue for disposal involves the lysosome pathway via autophagy. Enzymatic pathways include insulin degradative enzyme and neprilysin. Finally, the co-operative actions of C-terminus Hsp70 interacting protein (CHIP) and Parkin, components of a multiprotein E3 ubiquitin ligase complex, may be a portal to proteasome-mediated degradation. Mutations in the Parkin gene are the most common genetic link to autosomal recessive Parkinson’s disease. Parkin catalyzes the post-translational modification of proteins with polyubiquitin, targeting them to the 26S proteasome. Parkin reduces intracellular Aβ1–42 peptide levels, counteracts its effects on cell death, and reverses its effect to inhibit the proteasome. Additionally, Parkin has intrinsic cytoprotective activity to promote proteasome function and defend against oxidative stress to mitochondria. Parkin and CHIP are also active in amyloid clearance and cytoprotection in vivo. Parkin has cross-functionality in additional neurodegenerative diseases, for instance, to eliminate polyglutamine-expanded proteins, reducing their aggregation and toxicity and reinstate proteasome function. The dual actions of CHIP (molecular co-chaperone and E3 ligase) and Parkin (as E3-ubiquitin ligase and anti-oxidant) may also play a role in suppressing inflammatory reactions in animal models of neurodegeneration. In this review, we focus on the significance of CHIP and Parkin as inducers of amyloid clearance, as cytoprotectants and in the suppression of reactive inflammation. A case is made for more effort to explore whether neurodegeneration associated with proteinopathies can be arrested at early stages by promoting their mutual action.
    Journal of Neurochemistry 11/2011; 120(3):350-70. DOI:10.1111/j.1471-4159.2011.07588.x · 4.28 Impact Factor
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