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

Erin Bove-Fenderson, Ryo Urano, John E. Straub, David A. Harris

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


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 (PrPC) functions as a cell-surface receptor, which binds to A oligomers and transduces their toxic effects. However, the molecular details of the PrPC–A interaction remain uncertain. Here, we investigated the effect of PrPC 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 PrPC 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 PrPC, which has not been previously implicated in interactions with A. Our results suggest that PrPC 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 PrPC as a new and potentially more druggable molecular target for treating Alzheimer’s disease.

Original languageEnglish
Pages (from-to)16858-16871
Number of pages14
JournalJournal of Biological Chemistry
Issue number41
Publication statusPublished - Oct 13 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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