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