| First Author | Pietri M | Year | 2013 |
| Journal | Nat Med | Volume | 19 |
| Issue | 9 | Pages | 1124-31 |
| PubMed ID | 23955714 | Mgi Jnum | J:202038 |
| Mgi Id | MGI:5516529 | Doi | 10.1038/nm.3302 |
| Citation | Pietri M, et al. (2013) PDK1 decreases TACE-mediated alpha-secretase activity and promotes disease progression in prion and Alzheimer's diseases. Nat Med 19(9):1124-31 |
| abstractText | alpha-secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-beta (Abeta) peptides, and alpha-cleavage of cellular prion protein (PrP(C)) prevents its conversion into misfolded, pathogenic prions (PrP(Sc)). 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 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 Abeta 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 Abeta 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, PrP(C) and TNFR1, and attenuates PrP(Sc)- and Abeta-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. |
