Key residue for aggregation of amyloid-β peptides

Abstract Amyloid-b peptides (Abs) are associated with Alzheimer’s disease and have two isoforms: Ab40 and Ab42. Although the difference between Ab40 and Ab42 is only two additional C-terminal residues, Ab42 aggregates much faster and is more toxic than Ab40. It is unknown what role the C-terminal two residues play in accelerating aggregation. Clarifying the differences between the oligomerization processes of Ab40 and Ab42 is essential to elucidate the key factors of oligomerization. Performing Hamiltonian replica-permutation molecular dynamics simulations for Ab40 and Ab42 to investigate the early oligomerization process, we identified the key residue, Arg5, for the Ab42 dimerization. The two additional residues in Ab42 allow the C-terminus to form contact with Arg5, and this contact stabilizes the b-hairpin. This b-hairpin promotes the intermolecular b-bridge formation. We also conducted experiments on Ab aggregations to validate these simulation results and confirmed that mutations of Arg5 remarkably suppressed the Ab42 aggregation.