Prion protein stabilizes amyloid-β (Aβ) oligomers and enhances Aβ neurotoxicity in a Drosophila model of Alzheimer's disease

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