Abstract
The cellular prion protein (PrP(C)) can act as a cell-surface receptor for β-amyloid (Aβ) peptide; however, a role for PrP(C) in the pathogenesis of Alzheimer's disease (AD) is contested. Here, we expressed a range of Aβ isoforms and PrP(C) in the Drosophila brain. We found that co-expression of Aβ and PrP(C) significantly reduces the lifespan, disrupts circadian rhythms, and increases Aβ deposition in the fly brain. In contrast, under the same conditions, expression of Aβ or PrP(C) individually did not lead to these phenotypic changes. In vitro studies revealed that substoichiometric amounts of PrP(C) trap Aβ as oligomeric assemblies and fragment-preformed Aβ fibers. The ability of membrane-anchored PrP(C) to trap Aβ as cytotoxic oligomers at the membrane surface and fragment inert Aβ fibers suggests a mechanism by which PrP(C) exacerbates Aβ deposition and pathogenic phenotypes in the fly, supporting a role for PrP(C) in AD. This study provides a second animal model linking PrP(C) expression with Aβ toxicity and supports a role for PrP(C) in AD pathogenesis. Blocking the interaction of Aβ and PrP(C) represents a potential therapeutic strategy.