"Dual Disease" TgAD/GSS mice exhibit enhanced Alzheimer's disease pathology and reveal PrPC-dependent secretion of Aß.

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

Impaired transmissibility of atypical prions from genetic CJDG114V.

OBJECTIVE: To describe the clinicopathologic, molecular, and transmissible characteristics of genetic prion disease in a young man carrying the PRNP-G114V variant. METHODS: We performed genetic, histologic, and molecular studies, combined with in vivo transmission studies and in vitro replication studies, to characterize this genetic prion disease. RESULTS: A 24-year-old American man of Polish descent developed progressive dementia, aphasia, and ataxia, leading to his death 5 years later. Histologic features included widespread spongiform degeneration, gliosis, and infrequent PrP plaque-like deposits within the cerebellum and putamen, best classifying this as a Creutzfeldt-Jakob disease (CJD) subtype. Molecular typing of proteinase K-resistant PrP (resPrPSc) revealed a mixture of type 1 (∼21 kDa) and type 2 (∼19 kDa) conformations with only 2, rather than the usual 3, PrPSc glycoforms. Brain homogenates from the proband failed to transmit prion disease to transgenic Tg(HuPrP) mice that overexpress human PrP and are typically susceptible to sporadic and genetic forms of CJD. When subjected to protein misfolding cyclic amplification, the PrPSc type 2 (∼19 kDa) was selectively amplified. CONCLUSIONS: The features of genetic CJDG114V suggest that residue 114 within the highly conserved palindromic region (113-AGAAAAGA-120) plays an important role in prion conformation and propagation.