Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro.

ABSTRACT: Alzheimer's disease (AD) and Parkinson's disease (PD), including dementia with Lewy bodies (DLB), account for the majority of dementia cases worldwide. Interestingly, a significant number of patients have clinical and neuropathological features of both AD and PD, i.e., the presence of amyloid deposits and Lewy bodies in the neocortex. The identification of ?-synuclein peptides in amyloid plaques in DLB brain led to the hypothesis that both peptides mutually interact with each other to facilitate neurodegeneration. In this article, we report the influence of A?(1-42) and pGlu-A?(3-42) on the aggregation of ?-synuclein in vitro. The aggregation of human recombinant ?-synuclein was investigated using thioflavin-T fluorescence assay. Fibrils were investigated by means of antibody conjugated immunogold followed by transmission electron microscopy (TEM). Our data demonstrate a significantly increased aggregation propensity of ?-synuclein in the presence of minor concentrations of A?(1-42) and pGlu-A?(3-42) for the first time, but without effect on toxicity on mouse primary neurons. The analysis of the composition of the fibrils by TEM combined with immunogold labeling of the peptides revealed an interaction of ?-synuclein and A? in vitro, leading to an accelerated fibril formation. The analysis of kinetic data suggests that significantly enhanced nucleus formation accounts for this effect. Additionally, co-occurrence of ?-synuclein and A? and pGlu-A?, respectively, under pathological conditions was confirmed in vivo by double immunofluorescent labelings in brains of aged transgenic mice with amyloid pathology. These observations imply a cross-talk of the amyloid peptides ?-synuclein and A? species in neurodegeneration. Such effects might be responsible for the co-occurrence of Lewy bodies and plaques in many dementia cases.

SUBMITTER: Koppen J 

PROVIDER: S-EPMC7037551 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature