title: The cellular prion protein traps Alzheimer's Aβ in an oligomeric form and disassembles amyloid fibers.
abstract: There is now strong evidence to show that the presence of the cellular prion protein (PrP(C)) mediates amyloid-β (Aβ) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP(C) and Aβ and discover that substoichiometric amounts of PrP(C), as little as 1/20, relative to Aβ will strongly inhibit amyloid fibril formation. This effect is specific to the unstructured N-terminal domain of PrP(C). Electron microscopy indicates PrP(C) is able to trap Aβ in an oligomeric form. Unlike fibers, this oligomeric Aβ contains antiparallel β sheet and binds to a oligomer specific conformational antibody. Our NMR studies show that a specific region of PrP(C), notably residues 95-113, binds to Aβ oligomers, but only once Aβ misfolds. The ability of PrP(C) to trap and concentrate Aβ in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrP(C) might confer Aβ toxicity in AD, as oligomers are thought to be the toxic form of Aβ. Identification of a specific recognition site on PrP(C) that traps Aβ in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.
authors: School of Biological and Chemical Sciences, Queen Mary, University of London, London, UK.
authors: Nadine D
authors: ND
authors: Younan
authors: Claire J
authors: CJ
authors: Sarell
authors: Paul
authors: P
authors: Davies
authors: David R
authors: DR
authors: Brown
authors: John H
authors: JH
authors: Viles
mesh_terms: D000544:Alzheimer Disease; D000682:Amyloid / Q000737:chemistry* / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D000818:Animals; D001665:Binding Sites; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D018621:PrPC Proteins / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018621:PrPC Proteins