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

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2015 May 5

PMID 25938662

Citations 340

Authors

Yiling Xiao

Buyong Ma

Dan McElheny

Sudhakar Parthasarathy

Fei Long

Minako Hoshi

Ruth Nussinov

Yoshitaka Ishii

Affiliations

Soon will be listed here.

Abstract

Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1-42)), rather than of the more abundant Aβ(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1-42) have remained elusive. Here we present the atomic model of an Aβ(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1-40) fibrils. Remarkably, Aβ(1-40) is incompatible with the triple-β-motif, because seeding with Aβ(1-42) fibrils does not promote conversion of monomeric Aβ(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1-40). The results provide insight into the Aβ(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.

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