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

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 (PrP^Sc) 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 PrP^Sc. Importantly, brain Aβ deposition accelerates death of prion-infected mice. Our data stress that PrP^Sc, 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.