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

N.D. Younan, C.J. Sarell, P. Davies, D.R. Brown, J.H. Viles

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

There is now strong evidence to show that the presence of the cellular prion protein (PrPc) mediates amyloid-β (Aβ) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP and Aβ and discover that substoichiometric amounts of PrPc, 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 PrPc. Electron microscopy indicates PrPc 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 PrPc, notably residues 95-113, binds to Aβ oligomers, but only once Aβ misfolds. The ability of PrPc to trap and concentrate Aβ in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrPc might confer Aβ toxicity in AD, as oligomers are thought to be the toxic form of Aβ. Identification of a specific recognition site on PrPc that traps Aβ in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.

Original languageEnglish
Pages (from-to)1847-1858
Number of pages12
JournalFASEB Journal
Volume27
Issue number5
Early online date18 Jan 2013
DOIs
Publication statusPublished - May 2013

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