Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease

Nat Struct Mol Biol. 2015 Jun;22(6):499-505. doi: 10.1038/nsmb.2991. Epub 2015 May 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Folding*
  • Protein Multimerization*


  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-42)

Associated data

  • PDB/2MXU