PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases - Biological Adaptation and Ageing Accéder directement au contenu
Article Dans Une Revue Nature Medicine Année : 2013

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

Sophie Mouillet-Richard
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Jean-Marie Launay

Résumé

alpha-secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-beta (A beta) peptides, and alpha-cleavage of cellular prion protein (Pr-Pc) prevents its conversion into misfolded, pathogenic prions (PrPSc). The mechanisms leading to decreased alpha-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-alpha-converting enzyme (TACE)-mediated alpha-secretase activity is impaired at the surface of neurons infected with PrPSc 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 A beta deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-l-mediated internalization of TACE. This dysregulation of TACE increases PrPSc and A beta accumulation and reduces shedding of TNF-alpha receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent alpha-secretase activity and cleavage of APP, PrPC and TNFR1, and attenuates PrPSc- and A beta-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrPSc infection and in APP-transgenic mice reduces Alzheimer's disease-like pathology and memory impairment.
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Mathéa Pietri, Caroline Dakowski, Samia Hannaoui, Aurélie Alleaume-Butaux, Julia Hernandez-Rapp, et al.. PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases. Nature Medicine, 2013, 19 (9), pp.1124-1131. ⟨10.1038/nm.3302⟩. ⟨hal-02363130⟩
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