Neural Regeneration Research ›› 2022, Vol. 17 ›› Issue (9): 2072-2078.doi: 10.4103/1673-5374.335168

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(D-Ser2) oxyntomodulin recovers hippocampal synaptic structure and theta rhythm in Alzheimer’s disease transgenic mice

Guang-Zhao Yang1, #, Qi-Chao Gao2, #, Wei-Ran Li2, Hong-Yan Cai3, Hui-Min Zhao2, Jian-Ji Wang2, Xin-Rui Zhao2, Jia-Xin Wang2, Mei-Na Wu2, Jun Zhang4, Christian Hölscher5, Jin-Shun Qi2, *, Zhao-Jun Wang2, *   

  1. 1Department of Cardiovascular Medicine, the First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China; 2Department of Physiology, Shanxi Medical University; Key Laboratory of Cellular Physiology, Ministry of Education; Key Laboratory of Cellular Physiology in Shanxi Province, Taiyuan, Shanxi Province, China; 3Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi Province, China; 4Functional Laboratory Center, Shanxi Medical University, Taiyuan, Shanxi Province, China; 5Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China
  • Online:2022-09-15 Published:2022-03-08
  • Contact: Zhao-Jun Wang, wzhaojun1025@126.com; Jin-Shun Qi, jinshunqi2009@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 31600865 (to ZJW); “Sanjin Scholars” of Shanxi Province of China, No. [2016]7 (to MNW); Shanxi Province Science Foundation for Excellent Young Scholars of China, No. 201801D211005 (to MNW); the Applied Basic Research Program of Shanxi Province of China, No. 201901D111358 (to GZY); the Doctoral Startup Research Fund of Shanxi Medical University of China, No. 03201536 (to GZY); the Doctoral Startup Research Fund of the First Hospital of Shanxi Medical University of China, No. YJ1507 (to GZY); the National Undergraduate Innovation Program of China, No. 201910114019 (to JXW); and the Undergraduate Innovation Program of Shanxi Province of China, No. 2020189 (to XRZ).

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Abstract: In our previous studies, we have shown that (D-Ser2) oxyntomodulin (Oxm), a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide, protects hippocampal neurons against Aβ1–42-induced cytotoxicity, and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons. Additionally, we have demonstrated that (D-Ser2) Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer’s disease model mice. However, the protective mechanism remains unclear. In this study, we showed that 2 weeks of intraperitoneal administration of (D-Ser2) Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer’s disease model mice. In addition, electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that (D-Ser2) Oxm increased the power of the theta rhythm. In addition, (D-Ser2) Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer’s disease model mice. These findings suggest that (D-Ser2) Oxm improves the cognitive function of Alzheimer’s disease transgenic mice by recovering hippocampal synaptic function and theta rhythm. 

Key words: (D-ser2) oxyntomodulin, Alzheimer’s disease, cognitive decline, glucagon-like peptide-1, hippocampus, local field potential, synapse, theta rhythm