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"Dual Disease" TgAD/GSS mice exhibit enhanced Alzheimer's disease pathology and reveal PrP^C-dependent secretion of Aβ.

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 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.

SUBMITTER: Qin K

PROVIDER: S-EPMC6562043 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Qin Kefeng K Zhao Lili L Gregory Crystal C Solanki Ani A Mastrianni James A JA

Scientific reports 20190612 1

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 ...[more]

PMID: 31189938

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Project description:Prion diseases are fatal neurodegenerative diseases in mammals with the unique characteristics of misfolding and aggregation of the cellular prion protein (PrPC) to the scrapie prion (PrPSc). Although neuroinflammation and neuronal loss feature within the disease process, the details of PrPC/PrPSc molecular transition to generate different aggregated species, and the correlation between each species and sequence of cellular events in disease pathogenesis are not fully understood. In this study, using mice inoculated with the RML isolate of mouse-adapted scrapie as a model, we applied asymmetric flow field-flow fractionation to monitor PrPC and PrPSc particle sizes and we also measured seeding activity and resistance to proteases. For cellular analysis in brain tissue, we measured inflammatory markers and synaptic damage, and used the isotropic fractionator to measure neuronal loss; these techniques were applied at different timepoints in a cross-sectional study of disease progression. Our analyses align with previous reports defining significant decreases in PrPC levels at pre-clinical stages of the disease and demonstrate that these decreases become significant before neuronal loss. We also identified the earliest PrPSc assemblies at a timepoint equivalent to 40% elapsed time for the disease incubation period; we propose that these assemblies, mostly composed of proteinase K (PK)-sensitive species, play an important role in triggering disease pathogenesis. Lastly, we show that the PK-resistant assemblies of PrPSc that appear at timepoints close to the terminal stage have similar biophysical characteristics, and hence that preparative use of PK-digestion selects for this specific subpopulation. In sum, our data argue that qualitative, as well as quantitative, changes in PrP conformers occur at the midpoint of subclinical phase; these changes affect quaternary structure and may occur at the threshold where adaptive responses become inadequate to deal with pathogenic processes.

Dataset Information

"Dual Disease" TgAD/GSS mice exhibit enhanced Alzheimer's disease pathology and reveal PrP^C-dependent secretion of Aβ.

Publications

"Dual Disease" TgAD/GSS mice exhibit enhanced Alzheimer's disease pathology and reveal PrP<sup>C</sup>-dependent secretion of Aβ.

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