title: Single-molecule imaging reveals that small amyloid-β1-42 oligomers interact with the cellular prion protein (PrP(C)).
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK).
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Ganzinger
authors.forename: Priyanka
authors.initials: P
authors.lastname: Narayan
authors.forename: Seema S
authors.initials: SS
authors.lastname: Qamar
authors.forename: Laura
authors.initials: L
authors.lastname: Weimann
authors.forename: Rohan T
authors.initials: RT
authors.lastname: Ranasinghe
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: James
authors.initials: J
authors.lastname: McColl
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: David
authors.initials: D
authors.lastname: Klenerman
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D057054:Molecular Imaging; D010446:Peptide Fragments / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D011485:Protein Binding; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018621:PrPC Proteins; C075222:amyloid beta-protein (1-42)
keywords: amyloid beta-peptides; biophysics; neurochemistry; protein aggregation; single-molecule studies