4.6 Article

cPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated Tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus

Journal

NEUROSCIENCE BULLETIN
Volume 38, Issue 10, Pages 1153-1169

Publisher

SPRINGER
DOI: 10.1007/s12264-022-00863-4

Keywords

Conventional protein kinase C (cPKC)gamma; Tau; Phosphorylated Tau; Autophagy; AMPK/mTOR signaling pathway

Categories

Funding

  1. Beijing Natural Science Foundation [7192016, 7222064]
  2. Scientific Research Common Program of Beijing Municipal Commission of Education [KM201910025029]
  3. National Natural Science Foundation of China [82071539, 31972911]

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This study found that knockout of cPKCγ in the hippocampal neurons of T1DM mice increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles. cPKCγ deficiency reduced autophagy levels and cognitive impairment in T1DM mice. cPKCγ promotes autophagy through the AMPK/mTOR signaling pathway, reducing the phosphorylation of Tau at Ser214 and neurofibrillary tangles.
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)gamma significantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles, but did not affect the activities of GSK-3 beta and PP2A in the hippocampal neurons of T1DM mice. cPKC gamma deficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice. Activation of autophagy greatly alleviated the cognitive impairment induced by cPKC gamma deficiency in T1DM mice. Moreover, cPKC gamma 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 cPKC gamma promotes autophagy through the AMPK/mTOR signaling pathway, thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.

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