"Dual Disease" Tgad/Gss Mice Exhibit Enhanced Alzheimer'S Disease Pathology And Reveal Prpc-Dependent Secretion Of A Beta

To address the question of cross-talk between prion protein (PrP) and Alzheimer's disease (AD), we generated TgAD/GSS mice that develop amyloid-beta (A(beta) plaques of AD and PrP (specifically mutated PrPA116V) plaques of Gerstmann-Straussler-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-/-) PrPC. In contrast to PrPC, PrPA116V weakly co-localized to A beta plaques, did not co-immunoprecipitate with A beta, and poorly bound to A beta in an ELISA-based binding assay. Despite the reduced association of PrPA116V with A beta, TgAD/GSS and TgAD/HuPrP mice that express comparable levels of PrPA116V and PrPC respectively, displayed similar increases in A beta plaque burden and steady state levels of A beta and its precursor APP compared with TgAD mice. Our Tg mouse lines also revealed a predominance of intracellular A beta plaques in mice lacking PrPC(TgAD/PrP-/-, TgAD/GSS) compared with an extracellular predominance in PrPC-expressing mice (TgAD, TgAD/HuPrP). Parallel studies in N2aAPPswe cells revealed a direct dependence on PrPC but not PrPA116V for exosome-related secretion of A beta. Overall, our findings are two-fold; they suggest that PrP expression augments A beta 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 PrPC to bind to and deliver intraneuronal A beta to exosomes for secretion.