The non Amyloid-β Component (NAC) of Human α-Synuclein Oligomers Induces the Formation of New Aβ Oligomers: Insight into the Molecular Interactions that Link Parkinson's Disease and Alzheimer's Disease

Abstract

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) which are primarily composed of the Non Amyloid-β component (NAC) of α-Synuclein (AS). Clinical studies have identified the link between PD and Alzheimer's disease (AD), but the reason why PD patient have elevated risks towards developing AD remains unresolved. In vivo studies have shown that Aβ can act as seeds for AS aggregation, promoting AS aggregation and thus promote the etiology of PD. However, the molecular interactions by which AS oligomers self-assemble with Aβ oligomers remain elusive. The NAC segment plays a crucial role on AS aggregation, and was first purified from amyloid plaques in patients with AD. Our work presents the interactions between NAC oligomers and Aβ oligomers at the atomic resolution applying extensive molecular dynamics simulations for ensemble of cross-seeding NAC-Aβ1-42 oligomers. The main conclusions of this study are: First, the cross-seeding NAC-Aβ1-42 oligomers represent polymorphic states. Yet, NAC oligomers prefer to interact with Aβ1-42 oligomers to form double layer conformations over single layer conformations, due to electrostatic and hydrophobic interactions; Second, among the single layer conformations, the NAC oligomers induce the formation of new Aβ1-42 oligomers, thus leading to novel structures of Aβ oligomers; Third, NAC oligomers stabilize the cross-β structure of Aβ oligomers.