Cellular prion protein targets amyloid-β fibril ends via its C-terminal domain to prevent elongation

Oligomeric forms of the amyloid- (A) peptide are thought to represent the primary synaptotoxic species underlying the neurodegenerative changes seen in Alzheimer’s disease. It has been proposed that the cellular prion protein (PrP^C) functions as a cell-surface receptor, which binds to A oligomers and transduces their toxic effects. However, the molecular details of the PrP^C–A interaction remain uncertain. Here, we investigated the effect of PrP^C on polymerization of A under rigorously controlled conditions in which A converts from a monomeric to a fibrillar state via a series of kinetically defined steps. We demonstrated that PrP^C specifically inhibited elongation of A fibrils, most likely by binding to the ends of growing fibrils. Surprisingly, this inhibitory effect required the globular C-terminal domain of PrP^C, which has not been previously implicated in interactions with A. Our results suggest that PrP^C recognizes structural features common to both A oligomers and fibril ends and that this interaction could contribute to the neurotoxic effect of A aggregates. Additionally, our results identify the C terminus of PrP^C as a new and potentially more druggable molecular target for treating Alzheimer’s disease.