Structural Diversity of Alzheimer's Disease Amyloid-β Dimers and Their Role in Oligomerization and Fibril Formation

• Published in: Journal of Alzheimer's disease Vol. 39; no. 3; pp. 583 - 600
• Main Authors: Tsigelny, Igor F., Sharikov, Yuriy, Kouznetsova, Valentina L., Greenberg, Jerry P., Wrasidlo, Wolfgang, Gonzalez, Tania, Desplats, Paula, Michael, Sarah E., Trejo-Morales, Margarita, Overk, Cassia R., Masliah, Eliezer
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2014
• Subjects: Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - ultrastructure; Analysis of Variance; Animals; Cells, Cultured; Dimerization; Hippocampus - cytology; Humans; Microscopy, Electron; Models, Molecular; Molecular Dynamics Simulation; Neural Stem Cells - metabolism; Point Mutation - genetics; Protein Conformation; Protein Multimerization - physiology; Protein Structure, Secondary; Rats; neurodegeneration; Dimers; synaptoxicity; molecular dynamics; oligomers
• ISSN: 1387-2877; 1875-8908
• DOI: 10.3233/JAD-131589

Alzheimer's disease (AD) is associated with the formation of toxic amyloid-β (Aβ)42 oligomers, and recent evidence supports a role for Aβ dimers as building blocks for oligomers. Molecular dynamics simulation studies have identified clans for the dominant conformations of Aβ42 forming dimers; however, it is unclear if a larger spectrum of dimers is involved and which set(s) of dimers might evolve to oligomers verse fibrils. Therefore, for this study we generated multiple structural conformations of Aβ42, using explicit all-atom molecular dynamics, and then clustering the different structures based on key conformational similarities. Those matching a selection threshold were then used to model a process of oligomerization. Remarkably, we showed a greater diversity in Aβ dimers than previously described. Depending on the clan family, different types of Aβ dimers were obtained. While some had the tendency to evolve into oligomeric rings, others formed fibrils of diverse characteristics. Then we selected the dimers that would evolve to membranephilic annular oligomers. Nearly one third of the 28 evaluated annular oligomers had the dimer interfaces between the neighboring Aβ42 monomers with possible salt bridges between the residue K28 from one side and either residue E22 or D23 on the other. Based on these results, key amino acids were identified for point mutations that either enhanced or suppressed the formation and toxicity of oligomer rings. Our studies suggest a greater diversity of Aβ dimers. Understanding the structure of Aβ dimers might be important for the rationale design of small molecules that block formation of toxic oligomers.