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

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. Aβ plaques have been detected in brains of patients with prion diseases. Here, using mice, the authors show that prion infection enhances Aβ production via a PDK1-TACE mechanism and that brain deposition of Aβ induced by Aβ seeds co-transmitted with PrPSc contributes to mortality in prion disease.