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To address the question of cross-talk between prion protein (PrP) and Alzheimer’s disease (AD), we generated TgAD/GSS mice that develop amyloid-β (Aβ) plaques of AD and PrP (specifically mutated PrP A116V ) plaques of Gerstmann-Sträussler-Scheinker disease (GSS) and compared plaque-related features in these mice to AD mice that express normal (TgAD), high (TgAD/HuPrP), or no (TgAD/PrP −/− ) PrP C . In contrast to PrP C , PrP A116V  weakly co-localized to Aβ plaques, did not co-immunoprecipitate with Aβ, and poorly bound to Aβ in an ELISA-based binding assay. Despite the reduced association of PrP A116V  with Aβ, TgAD/GSS and TgAD/HuPrP mice that express comparable levels of PrP A116V  and PrP C  respectively, displayed similar increases in Aβ plaque burden and steady state levels of Aβ and its precursor APP compared with TgAD mice. Our Tg mouse lines also revealed a predominance of intracellular Aβ plaques in mice lacking PrP C  (TgAD/PrP −/− , TgAD/GSS) compared with an extracellular predominance in PrP C -expressing mice (TgAD, TgAD/HuPrP). Parallel studies in N2aAPPswe cells revealed a direct dependence on PrP C  but not PrP A116V  for exosome-related secretion of Aβ. Overall, our findings are two-fold; they suggest that PrP expression augments Aβ plaque production, at least in part by an indirect mechanism, perhaps by increasing steady state levels of APP, while they also provide support for a fundamental role of PrP C  to bind to and deliver intraneuronal Aβ to exosomes for secretion.

“Dual Disease” TgAD/GSS mice exhibit enhanced Alzheimer’s disease pathology and reveal PrPC-dependent secretion of Aβ