Amylin–Aβ oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease

Abstract

Clinical studies have identified Type 2 diabetes (T2D) as a risk factor of Alzheimer's disease (AD). One of the potential mechanisms that link T2D and AD is the loss of cells associated with degenerative changes. Amylin_1–37 aggregates (the pathological species in T2D) were found to be co-localized with those of Aβ_1–42 (the pathological species in AD) to form the Amylin_1–37–Aβ_1–42 plaques, promoting aggregation and thus contributing to the etiology of AD. However, the mechanisms by which Amylin_1–37 co-aggregates with Aβ_1–42 are still elusive. This work presents the interactions between Amylin_1–37 oligomers and Aβ_1–42 oligomers at atomic resolution applying extensive molecular dynamics simulations for relatively large ensemble of cross-seeding Amylin_1–37–Aβ_1–42 oligomers. The main conclusions of this study are first, Aβ_1–42 oligomers prefer to interact with Amylin_1–37 oligomers to form single layer conformations (in-register interactions) rather than double layer conformations; and second, in some double layer conformations of the cross-seeding Amylin_1–37–Aβ_1–42 oligomers, the Amylin_1–37 oligomers destabilize the Aβ_1–42 oligomers and thus inhibit Aβ_1–42 aggregation, while in other double layer conformations, the Amylin_1–37 oligomers stabilize Aβ_1–42 oligomers and thus promote Aβ_1–42 aggregation.