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