PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases

Nat Med. 2013 Sep;19(9):1124-31. doi: 10.1038/nm.3302. Epub 2013 Aug 18.

Abstract

α-secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-β (Aβ) peptides, and α-cleavage of cellular prion protein (PrP(C)) prevents its conversion into misfolded, pathogenic prions (PrP(Sc)). The mechanisms leading to decreased α-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-α-converting enzyme (TACE)-mediated α-secretase activity is impaired at the surface of neurons infected with PrP(Sc) or isolated from APP-transgenic mice with amyloid pathology. 3-phosphoinositide-dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by Aβ deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-1-mediated internalization of TACE. This dysregulation of TACE increases PrP(Sc) and Aβ accumulation and reduces shedding of TNF-α receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent α-secretase activity and cleavage of APP, PrP(C) and TNFR1, and attenuates PrP(Sc)- and Aβ-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrP(Sc) infection and in APP-transgenic mice reduces Alzheimer's disease-like pathology and memory impairment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Caveolin 1 / metabolism
  • Cell Survival
  • Cells, Cultured
  • Disease Progression
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation
  • Prion Diseases / metabolism*
  • Prions / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Caveolin 1
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Prions
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse