Amylin-Aβ oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and
Michal Baram1, Yoav Atsmon-Raz1, Buyong Ma2
1Department of Chemistry, Ben-Gurion University of the Negev, Beér-Sheva 84105, Israel and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beér-Sheva 84105, Israel. ymiller@bgu.ac.il.
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. Amylin1-37 aggregates (the pathological species in T2D) were found to be co-localized with those of Aβ1-42 (the pathological species in AD) to form the Amylin1-37-Aβ1-42 plaques, promoting aggregation and thus contributing to the etiology of AD. However, the mechanisms by which Amylin1-37 co-aggregates with Aβ1-42 are still elusive. This work presents the interactions between Amylin1-37 oligomers and Aβ1-42 oligomers at atomic resolution applying extensive molecular dynamics simulations for relatively large ensemble of cross-seeding Amylin1-37-Aβ1-42 oligomers. The main conclusions of this study are first, Aβ1-42 oligomers prefer to interact with Amylin1-37 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 Amylin1-37-Aβ1-42 oligomers, the Amylin1-37 oligomers destabilize the Aβ1-42 oligomers and thus inhibit Aβ1-42 aggregation, while in other double layer conformations, the Amylin1-37 oligomers stabilize Aβ1-42 oligomers and thus promote Aβ1-42 aggregation.
Insights
Type 2 diabetes (T2D) and Alzheimer's disease (AD) link through amylin and amyloid-beta aggregation. Molecular dynamics reveal amylin can either inhibit or promote Alzheimer's-related protein aggregation.
Area of Science:
- Neuroscience
- Biochemistry
- Computational Biology
Background:
- Type 2 diabetes (T2D) is a known risk factor for Alzheimer's disease (AD).
- Degenerative cellular changes and protein aggregation are implicated in both diseases.
- Amylin (pathological in T2D) and amyloid-beta (Aβ, pathological in AD) co-localize, forming plaques that may contribute to AD pathogenesis.
Purpose of the Study:
- To elucidate the atomic-level mechanisms of co-aggregation between amylin1-37 and Aβ1-42 oligomers.
- To investigate how these cross-seeding interactions influence protein aggregation dynamics.
Main Methods:
- Extensive molecular dynamics (MD) simulations were employed.
- Simulations focused on relatively large ensembles of cross-seeding amylin1-37-Aβ1-42 oligomers.
- Atomic resolution analysis of inter-oligomer interactions was performed.
Main Results:
- Aβ1-42 oligomers showed a preference for interacting with amylin1-37 oligomers to form single-layer, in-register conformations.
- In double-layer conformations, amylin1-37 oligomers exhibited dual roles: destabilizing Aβ1-42 in some instances, thereby inhibiting aggregation.
- Conversely, in other double-layer arrangements, amylin1-37 oligomers stabilized Aβ1-42, promoting aggregation.
Conclusions:
- The interaction between amylin1-37 and Aβ1-42 oligomers is complex, influencing aggregation pathways.
- Amylin's role in AD pathogenesis may depend on the specific conformational arrangements of co-aggregates.
- Understanding these molecular interactions provides insights into the T2D-AD link and potential therapeutic targets.
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