Amylin-Aβ oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease.
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.
Department 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.
Michal
M
Baram
Department 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.
Yoav
Y
Atsmon-Raz
Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA. NussinoR@helix.nih.gov.
Buyong
B
Ma
Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA. NussinoR@helix.nih.gov and Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Ruth
R
Nussinov
Department 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.
Yifat
Y
Miller
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001704:Biopolymers / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)