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

摘要

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 A beta(1-42) (the pathological species in AD) to form the Amylin(1-37)-A beta(1-42) plaques, promoting aggregation and thus contributing to the etiology of AD. However, the mechanisms by which Amylin(1-37) co-aggregates with A beta(1-42) are still elusive. This work presents the interactions between Amylin(1-37) oligomers and A beta(1-42) oligomers at atomic resolution applying extensive molecular dynamics simulations for relatively large ensemble of cross-seeding Amylin(1-37)-A beta(1-42) oligomers. The main conclusions of this study are first, A beta(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)-A beta(1-42) oligomers, the Amylin(1-37) oligomers destabilize the A beta(1-42) oligomers and thus inhibit A beta(1-42) aggregation, while in other double layer conformations, the Amylin(1-37) oligomers stabilize A beta(1-42) oligomers and thus promote A beta(1-42) aggregation.