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The cellular prion protein traps Alzheimer's A? 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-? (A?) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP(C) and A? and discover that substoichiometric amounts of PrP(C), as little as 1/20, relative to A? 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 A? in an oligomeric form. Unlike fibers, this oligomeric A? contains antiparallel ? 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 A? oligomers, but only once A? misfolds. The ability of PrP(C) to trap and concentrate A? in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrP(C) might confer A? toxicity in AD, as oligomers are thought to be the toxic form of A?. Identification of a specific recognition site on PrP(C) that traps A? in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.

SUBMITTER: Younan ND 

PROVIDER: S-EPMC3767752 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Younan Nadine D ND   Sarell Claire J CJ   Davies Paul P   Brown David R DR   Viles John H JH  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130118 5


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 tra  ...[more]

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