Production of seedable Amyloid-β peptides in model of prion diseases upon PrP Sc-induced PDK1 overactivation

Nat Commun. 2019 Aug 1;10(1):3442. doi: 10.1038/s41467-019-11333-3.

Abstract

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 (PrPSc) 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 monomers, but is also found as trimers and tetramers. Prion-induced Aβ peptides do not affect prion replication and infectivity, but display seedable properties as they can deposit in the mouse brain only when seeds of Aβ trimers are co-transmitted with PrPSc. Importantly, brain Aβ deposition accelerates death of prion-infected mice. Our data stress that PrPSc, through deregulation of the PDK1-TACE-APP pathway, provokes the accumulation of Aβ, a prerequisite for the onset of an Aβ seeds-induced Aβ pathology within a prion-infectious context.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein / metabolism
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Behavior, Animal
  • Brain / metabolism
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurodegenerative Diseases / metabolism
  • Neurons / metabolism
  • Peptide Fragments / cerebrospinal fluid
  • Plaque, Amyloid / metabolism
  • Prion Diseases / cerebrospinal fluid
  • Prion Diseases / metabolism*
  • Prion Diseases / pathology
  • Prions / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism*
  • Stem Cells

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Pdk1 protein, mouse
  • Peptide Fragments
  • Prions
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • amyloid beta-protein (40-42)
  • Amyloid Precursor Protein Secretases
  • ADAM17 Protein
  • Adam17 protein, mouse