cPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated Tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus
Jiayin Zheng1 • Yue Wang2,3 • Yue Liu1 • Song Han1 • Ying Zhang1 • Yanlin Luo1 • Yi Yan1 • Junfa Li1 • Li Zhao11 Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
2 The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China
3 Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100088, China
Abstract
Type 1 diabetes mellitus (T1DM)-induced cognitive dysfunction is common, but its underlying mechanisms are still poorly understood. In this study, we found that knockout of conventional protein kinase C (cPKC)γ significantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles, but did not affect the activities of GSK-3β and PP2A in the hippocampal neurons of T1DM mice. cPKCγ deficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice. Activation of autophagy greatly alleviated the cognitive impairment induced by cPKCγ deficiency in T1DM mice. Moreover, cPKCγ deficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in vitro. The high glucose-induced Tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR inhibitor. In conclusion, these results indicated that cPKCγ promotes autophagy through the AMPK/mTOR signaling pathway, thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.
Keywords
Conventional protein kinase C (cPKC)γ; Tau; Phosphorylated Tau; Autophagy; AMPK/mTOR signaling pathway
