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  3. High glucose- or AGE-induced oxidative stress inhibits hippocampal neuronal mitophagy through the Keap1-Nrf2-PHB2 pathway in diabetic encephalopathy

High glucose- or AGE-induced oxidative stress inhibits hippocampal neuronal mitophagy through the Keap1-Nrf2-PHB2 pathway in diabetic encephalopathy

  • Sci Rep. 2024 Oct 14;14(1):24044. doi: 10.1038/s41598-024-70584-3.
Shan Xu 1 2,  Zhaoyu Gao 1 3 4,  Lei Jiang 1 3 4,  Jiazheng Li 1,  Yushi Qin 1,  Di Zhang 1,  Pei Tian 1,  Wanchang Wang 1,  Nan Zhang 1 3 4,  Rui Zhang 5 6 7,  Shunjiang Xu 8 9 10
Affiliations

Affiliations

  • 1 Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China.
  • 2 Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China.
  • 3 Hebei International Joint Research Center for Brain Science, Shijiazhuang, 050031, People's Republic of China.
  • 4 Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, 050031, People's Republic of China.
  • 5 Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China. zhangrui1981@hebmu.edu.cn.
  • 6 Hebei International Joint Research Center for Brain Science, Shijiazhuang, 050031, People's Republic of China. zhangrui1981@hebmu.edu.cn.
  • 7 Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, 050031, People's Republic of China. zhangrui1981@hebmu.edu.cn.
  • 8 Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China. xushunjiang@hebmu.edu.cn.
  • 9 Hebei International Joint Research Center for Brain Science, Shijiazhuang, 050031, People's Republic of China. xushunjiang@hebmu.edu.cn.
  • 10 Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, 050031, People's Republic of China. xushunjiang@hebmu.edu.cn.
PMID: 39402106 DOI: 10.1038/s41598-024-70584-3
Abstract

Diabetic encephalopathy (DE) is a severe complication of diabetes, but its pathogenesis remains unclear. This study aimed to investigate the roles and underlying mechanisms of high glucose (HG)- and advanced glycosylation end product (AGE)-induced oxidative stress (OS) in the cognitive decline in DE. The DE mouse model was established using a high-fat diet and streptozotocin, and its cognitive functions were evaluated using the Morris Water Maze, novel object recognition, and Y-maze test. The results revealed increased Reactive Oxygen Species (ROS) generation, Mitophagy inhibition, and decreased prohibitin 2 (PHB2) expression in the hippocampal neurons of DE mice and HG- or AGE-treated HT-22 cells. However, overexpression of PHB2 reduced ROS generation, reversed Mitophagy inhibition, and improved mitochondrial function in the HG- or AGE-treated HT-22 cells and ameliorated cognitive decline, improved mitochondrial structural damage, and reversed Mitophagy inhibition of hippocampal neurons in DE mice. Further analysis revealed that the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the HG- or AGE-mediated downregulation of PHB2 in HT-22 cells. These results demonstrate that HG- or AGE-induced OS inhibits the Mitophagy of hippocampal neurons via the Keap1-Nrf2-PHB2 pathway, thereby contributing to the cognitive decline in DE.

Keywords

Advanced glycosylation end products; Diabetic encephalopathy; High glucose; Mitophagy; Prohibitin 2.

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