The cellular prion protein traps Alzheimer's Aβ in an oligomeric form and disassembles amyloid fibers

There is now strong evidence to show that the presence of the cellular prion protein (PrPC) mediates amyloid-beta (A beta) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrPC and A beta and discover that substoichiometric amounts of PrPC, as little as 1/20, relative to A beta will strongly inhibit amyloid fibril formation. This effect is specific to the unstructured N-terminal domain of PrPC. Electron microscopy indicates PrPC is able to trap A beta in an oligomeric form. Unlike fibers, this oligomeric A beta contains antiparallel beta sheet and binds to a oligomer specific conformational antibody. Our NMR studies show that a specific region of PrPC, notably residues 95-113, binds to A beta oligomers, but only once A beta misfolds. The ability of PrPC to trap and concentrate A beta in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrPC might confer A beta toxicity in AD, as oligomers are thought to be the toxic form of A beta. Identification of a specific recognition site on PrPC that traps A beta in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.-Younan, N. D., Sarell, C. J., Davies, P., Brown, D. R., Viles, J. H. The cellular prion protein traps Alzheimer's A beta in an oligomeric form and disassembles amyloid fibers. FASEB J. 27, 1847-1858 (2013). www.fasebj.org