Single-Molecule Imaging Reveals that Small Amyloid-β1-42 Oligomers Interact with the Cellular Prion Protein (PrPC)

Oligomers of the amyloid-beta peptide (A beta) 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 A beta 42 have obscured the nature of the oligomeric species that bind to a given receptor. Here, we have used single-molecule imaging to characterize A beta 42 oligomers (oA beta 42) and to confirm the controversial interaction of oA beta 42 with the cellular prion protein (PrPC) on live neuronal cells. Our results show that, at nanomolar concentrations, oA beta 42 interacts with PrPC and that the species bound to PrPC are predominantly small oligomers (dimers and trimers). Single-molecule biophysical studies can thus aid in deciphering the mechanisms that underlie receptor-mediated oA beta-induced neurotoxicity, and ultimately facilitate the discovery of novel inhibitors of these pathways.