Dataset Information

Production of seedable Amyloid-? peptides in model of prion diseases upon PrPSc-induced PDK1 overactivation.

ABSTRACT: The presence of amyloid beta (A?) plaques in the brain of some individuals with Creutzfeldt-Jakob or Gertsmann-Straussler-Scheinker diseases suggests that pathogenic prions (PrPSc) would have stimulated the production and deposition of A? peptides. We here show in prion-infected neurons and mice that deregulation of the PDK1-TACE ?-secretase pathway reduces the Amyloid Precursor Protein (APP) ?-cleavage in favor of APP ?-processing, leading to A?40/42 accumulation. A? predominates as monomers, but is also found as trimers and tetramers. Prion-induced A? peptides do not affect prion replication and infectivity, but display seedable properties as they can deposit in the mouse brain only when seeds of A? trimers are co-transmitted with PrPSc. Importantly, brain A? deposition accelerates death of prion-infected mice. Our data stress that PrPSc, through deregulation of the PDK1-TACE-APP pathway, provokes the accumulation of A?, a prerequisite for the onset of an A? seeds-induced A? pathology within a prion-infectious context.

SUBMITTER: Ezpeleta J

PROVIDER: S-EPMC6672003 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Production of seedable Amyloid-β peptides in model of prion diseases upon PrP<sup>Sc</sup>-induced PDK1 overactivation.

Ezpeleta Juliette J Baudouin Vincent V Arellano-Anaya Zaira E ZE Boudet-Devaud François F Pietri Mathéa M Baudry Anne A Haeberlé Anne-Marie AM Bailly Yannick Y Kellermann Odile O Launay Jean-Marie JM Schneider Benoit B

Nature communications 20190801 1

The presence of amyloid beta (Aβ) plaques in the brain of some individuals with Creutzfeldt-Jakob or Gertsmann-Straussler-Scheinker diseases suggests that pathogenic prions (PrP<sup>Sc</sup>) would have stimulated the production and deposition of Aβ peptides. We here show in prion-infected neurons and mice that deregulation of the PDK1-TACE α-secretase pathway reduces the Amyloid Precursor Protein (APP) α-cleavage in favor of APP β-processing, leading to Aβ40/42 accumulation. Aβ predominates as ...[more]

PMID: 31371707

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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

Production of seedable Amyloid-? peptides in model of prion diseases upon PrPSc-induced PDK1 overactivation.

Publications

Production of seedable Amyloid-β peptides in model of prion diseases upon PrP<sup>Sc</sup>-induced PDK1 overactivation.

Similar Datasets

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