资源环境科技发展态势分析平台

The presence of amyloid beta (A beta) 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 beta peptides. We here show in prion-infected neurons and mice that deregulation of the PDK1-TACE alpha-secretase pathway reduces the Amyloid Precursor Protein (APP) alpha-cleavage in favor of APP beta-processing, leading to A beta 40/42 accumulation. A beta predominates as monomers, but is also found as trimers and tetramers. Prion-induced A beta 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 beta trimers are co-transmitted with PrPSc. Importantly, brain A beta 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 beta, a prerequisite for the onset of an A beta seeds-induced A beta pathology within a prion-infectious context.