Alpha-secretase-mediated processing of cellular prion protein and amyloid precursor protein is decreased in prion and Alzheimer’s diseases. In this paper, Pietri and colleagues show that activity of the kinase PDK1 is increased in the brain following prion infection and with amyloid pathology. This results in internalization of tumor necrosis factor-α-converting enzyme TACE and impairs TACE-mediated alpha-secretase activity. The authors show that inhibition of PDK1 is beneficial in mouse models of prion infection and Alzheimer’s disease, suggesting that PDK1 may be a therapeutic target for attenuation of disease progression. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following pathogenic prion PrPSc infection and in APP-transgenic mice there is a reduction in Alzheimer’s disease-like pathology and memory impairment.
Pietri M, Dakowski C, Hannaoui S, Alleaume-Butaux A, Hernandez-Rapp J, Ragagnin A, Mouillet-Richard S, Haik S, Bailly Y, Peyrin JM, Launay JM, Kellermann O, Schneider B: PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. Nature Medicine [Epub ahead of print, August 18, 2013, doi: 10.1038/nm.3302].