The Effects of Amyloid-Beta 42 Oligomers on Alpha-synuclein Clearance
Abstract
Parkinson's Disease (PD) and Dementia with Lewy Body (DLB) are neurodegenerative disorders characterized by the accumulation and aggregation of α-synuclein (α-syn) into Lewy Bodies, resulting in neuronal dysfunction and cell death. Beta-amyloid (Aβ), an Alzheimer’s Disease protein, is associated with accelerated dementia progression in DLB, and it could be an important feature distinguishing PD from DLB. However, the interactions of Aβ and α-syn remain unclear. Aβ42 oligomers (Aβ42o) are known to impair parts of the autophagy-lysosomal pathway (ALP), a key mechanism for α-syn clearance. We hypothesized that Aβ42o disrupts ALP function, leading to α-syn accumulation and aggregation. In this study, we assess the impact of Aβ42o on ALP function and clearance of α-syn in N2a cells expressing human α-syn. Our findings reveal that Aβ42o hinders autophagosomal sequestration of α-syn and reduces its lysosomal accumulation. Poisoning autophagy could be an important mechanism leading to the deposition of α-syn. These findings contribute to understanding the mechanisms of disease initiation in PD and LBD, providing potential targets for therapeutic interventions.