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

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.