Emx1-Cre-mediated inactivation of PDK1 prevents plaque deposition in an Alzheimer’s disease-like mouse model

Abstract

BX912, an inhibitor for 3-phosphoinositide-dependent protein kinase 1 (PDK1), has been shown to produce beneficial effects in mouse models of Alzheimer’s disease (AD). To test the hypothesis that early inhibition on PDK1 may prevent neuropathology in a 5×FAD mouse model, we employed a genetic approach to generate a mutant line, termed as Pdk1 cKO/5×FAD, in which PDK1 is inactivated, specifically in the developing cortex of 5×FAD mice through Emx1-Cre-mediated gene recombination. We discovered that the Pdk1 cKO/5×FAD mice exhibited a massive reduction of plaque pathology compared with their 5×FAD littermates. We also demonstrated that gliosis was remarkably attenuated in Pdk1 cKO/5×FAD cortices and amyloid precursor protein levels were significantly lower in Pdk1 cKO/5×FAD cortices compared with 5×FAD littermates. This study suggests that early inhibition on PDK1 may effectively prevent AD-like neuropathology.