title: PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases.
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.
authors: 1] Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 747, Paris, France. [2] Université Paris Descartes, Sorbonne Paris Cité, UMR-S 747, Paris, France.
authors: Mathéa
authors: M
authors: Pietri
authors: Caroline
authors: C
authors: Dakowski
authors: Samia
authors: S
authors: Hannaoui
authors: Aurélie
authors: A
authors: Alleaume-Butaux
authors: Julia
authors: J
authors: Hernandez-Rapp
authors: Audrey
authors: A
authors: Ragagnin
authors: Sophie
authors: S
authors: Mouillet-Richard
authors: Stéphane
authors: S
authors: Haik
authors: Yannick
authors: Y
authors: Bailly
authors: Jean-Michel
authors: JM
authors: Peyrin
authors: Jean-Marie
authors: JM
authors: Launay
authors: Odile
authors: O
authors: Kellermann
authors: Benoit
authors: B
authors: Schneider
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D017096:Prion Diseases / Q000378:metabolism*; D011328:Prions / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051242:Caveolin 1; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D011328:Prions; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
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