Production of seedable Amyloid-β peptides in model of prion diseases upon PrP-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 (PrP) 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.

Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase.

Although cellular prion protein PrP is well known for its implication in Transmissible Spongiform Encephalopathies, its functions remain elusive. Combining in vitro and in vivo approaches, we here show that PrP displays the intrinsic capacity to protect neuronal cells from a pro-inflammatory TNFα noxious insult. Mechanistically, PrP coupling to the NADPH oxidase-TACE α-secretase signaling pathway promotes TACE-mediated cleavage of transmembrane TNFα receptors (TNFRs) and the release of soluble TNFR, which limits the sensitivity of recipient cells to TNFα.

Cerebellar compartmentation of prion pathogenesis.

In prion diseases, the brain lesion profile is influenced by the prion "strain" properties, the invasion route to the brain, and still unknown host cell-specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP , PrP ), but not bovine spongiform encephalopathy PrP , accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice.