Evaluating the relationship between amyloid-β and aα-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson's disease

Abstract

Introduction: Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and aα-synuclein (aα-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of aα-syn at serine-129 (pSer129 aα-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human aα-syn. Methods: We measured levels of Aβ40, Aβ42, aα-syn and pSer129 aα-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. Results: In most brain regions, the concentration of insoluble pSer129 aα-syn correlated positively, and soluble pSer129 aα-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 aα-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble aα-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 aα-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of aα-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect). Conclusions: Together, these data show that the concentration of pSer129 aα-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.