Abstract
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 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 Aβ plaques, did not co-immunoprecipitate with Aβ, and poorly bound to Aβ in an ELISA-based binding assay. Despite the reduced association of PrPA116V with Aβ, TgAD/GSS and TgAD/HuPrP mice that express comparable levels of PrPA116V and PrPC 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 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 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 PrPC to bind to and deliver intraneuronal Aβ to exosomes for secretion.
Highlights
Key histopathological hallmarks of Alzheimer’s disease (AD) are the accumulation of extracellular amyloid-β (Aβ) plaque deposits and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau[1,2]
A subsequent report found no effect on Aβ or amyloid precursor protein (APP) levels when the prion protein (PrP) gene (Prnp) was deleted from an AD mouse model that expresses APP with the Swedish mutation (APPswe) and the exon 9 deletion of presenilin-1 (PS-1ΔE9), they did find that synaptic degeneration was reduced and spatial memory was better preserved compared with the parental line[4], suggesting a disease-enhancing effect of PrPC
We provide additional evidence that cross-talk occurs between prion disease (PrD) and AD, our results question cross-seeding as the principal mechanism by which PrP augments Aβ plaque production
Summary
Key histopathological hallmarks of Alzheimer’s disease (AD) are the accumulation of extracellular amyloid-β (Aβ) plaque deposits and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau[1,2]. In mice with an ablated APP gene, a 13% delay in onset of PrD following inoculation of mouse-adapted sheep scrapie was reported[11], suggesting APP, or a fragment of it, might promote PrD Another group found enhanced PrD-related pathology in an AD mouse model inoculated with scrapie compared with scrapie-infected non-Tg mice[12]. Www.nature.com/scientificreports pathology, but that analysis concluded that AD does not promote PrD pathology[16] Based on these conflicting studies we chose to re-examine the inter-relationship between AD and PrD by generating a Tg mouse that simultaneously develops extracellular deposits of Aβ and PrP amyloid. TgGSS mice that express mouse PrPA116V, the mouse homolog of human PrPA117V known to cause GSS17, were crossed with a previously established mouse model of AD that co-expresses human APPswe and PS-1ΔE9 transgenes[18] Our studies with these mice provide two distinct findings. Our studies reveal an important new function of PrPC to facilitate secretion of intraneuronal Aβ via exosomes
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