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