Single-molecule imaging reveals that small amyloid-β1-42 oligomers interact with the cellular prion protein (PrP(C))

Chembiochem. 2014 Nov 24;15(17):2515-21. doi: 10.1002/cbic.201402377. Epub 2014 Oct 7.

Abstract

Oligomers of the amyloid-β peptide (Aβ) play a central role in the pathogenesis of Alzheimer's disease and have been suggested to induce neurotoxicity by binding to a plethora of cell-surface receptors. However, the heterogeneous mixtures of oligomers of varying sizes and conformations formed by Aβ42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single-molecule imaging to characterize Aβ42 oligomers (oAβ42) and to confirm the controversial interaction of oAβ42 with the cellular prion protein (PrP(C)) on live neuronal cells. Our results show that, at nanomolar concentrations, oAβ42 interacts with PrP(C) and that the species bound to PrP(C) are predominantly small oligomers (dimers and trimers). Single-molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor-mediated oAβ-induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways.

Keywords: amyloid beta-peptides; biophysics; neurochemistry; protein aggregation; single-molecule studies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Humans
  • Molecular Imaging*
  • Peptide Fragments / metabolism*
  • PrPC Proteins / metabolism*
  • Protein Binding
  • Tumor Cells, Cultured

Substances

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