Abstract
IntroductionLewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn.MethodsWe measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson’s disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage.ResultsIn most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).ConclusionsTogether, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-014-0077-y) contains supplementary material, which is available to authorized users.
Highlights
Lewy body and Alzheimer-type pathologies often co-exist
Case selection We studied 35 cases of Parkinson’s disease (PD) (23 Parkinson’s disease without dementia (PDND) and 12 Parkinson’s disease (PD) with (PDD)) from the Queen Square Brain Bank (QSBB) for Neurological Disorders, University College London (UCL) Institute of Neurology, London, and 10 cases of dementia with Lewy bodies (DLB) and 17 age-matched controls from the South West Dementia Brain Bank (SWDBB), University of Bristol (Table 1)
The pSer129 α-syn antibody labelled α-syn following incubation with casein kinase II (CKII), and to a lesser extent casein kinase I (CKI), but did not label recombinant α-syn that had not been phosphorylated with CKI or CKII
Summary
Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. In PD and DLB, the number of cortical α-syn aggregates is significantly higher in patients who have Aβ plaques in the cortex [25,26] and α-syn accumulates within some plaque-associated dystrophic neurites [27] Transgenic mice expressing both Aβ and α-syn had more Lewy body pathology and more severe deficits in learning and memory than did mice expressing α-syn alone [28]. It is noteworthy that the most frequent form of pathological overlap between Lewy body diseases and AD is the presence of increased numbers of Aβ plaques in PDD and DLB [25,33], with limited formation of tangles and the interactions between α-syn and Aβ were, the primary focus of this study
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