Aβ(1–42) Fibril Structure Illuminates Self-recognition and Replication of Amyloid in Alzheimer’s

Increasing evidence suggests that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1–42)), rather than the more abundant Aβ(1–40), provokes the Alzheimer’s cascade. To date, structural details of misfolded Aβ(1–42) have remained elusive. Here we present the atomic model of Aβ(1–42) amyloid fibril based on solid-state NMR (SSNMR) data. It displays triple parallel-β-sheet segments that are different from reported structures of Aβ(1–40) fibrils. Remarkably, Aβ(1–40) is not compatible with the triple-β motif, as seeding with Aβ(1–42) fibrils does not promote conversion of monomeric Aβ(1–40) into fibrils via cross-replication. SSNMR experiments suggest that the Ala42 carboxyl terminus, absent in Aβ(1–40), forms a salt-bridge with Lys28 as a self-recognition molecular switch that excludes Aβ(1–40). The results provide insight into Aβ(1–42)-selective self-replicating amyloid propagation machinery in early-stage Alzheimer’s disease.