中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (9): 2072-2078.doi: 10.4103/1673-5374.335168

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

(D-Ser2)胃泌酸调节素可恢复阿尔茨海默病转基因小鼠的海马突触功能及theta节律

  

  • 出版日期:2022-09-15 发布日期:2022-03-08

(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).

摘要:

作者既往研究发现,(D-Ser2)胃泌酸调节素是一种新型胰高血糖素样肽1和胰高血糖素双重受体激动剂,可稳定海马神经元的钙稳态和线粒体膜电位,并有效拮抗淀粉样蛋白β的细胞毒性。虽然已有研究证实其可改善阿尔茨海默病小鼠的认知能力并减少β淀粉样蛋白的沉积,但其保护机制尚不明确。因此实验对9个月龄3xTg阿尔茨海默病小鼠连续2周腹腔注射(D-Ser2)胃泌酸调节素,结果显示,其可有效减轻小鼠的工作记忆和恐惧记忆障碍。置入海马CA1区的无线多通道神经记录系统发现,(D-Ser2)胃泌酸调节素可增加小鼠海马增加theta节律的强度;同时经(D-Ser2)胃泌酸调节素治疗的3xTg阿尔茨海默病小鼠突触相关蛋白突触素和突触后密度蛋白95的表达水平明显降低,而海马CA1区树突棘数量增加。由此说明(D-Ser2)胃泌酸调节素可通过恢复阿尔茨海默病转基因小鼠的海马突触功能以及theta节律以改善其认知功能。

https://orcid.org/0000-0001-7289-5307 (Zhao-Jun Wang); https://orcid.org/0000-0001-9223-8806 (Jin-Shun Qi)

关键词: 阿尔茨海默病, 胰高血糖素样肽1, (D-ser2)胃泌酸调节素, 认知功能, theta节奏, 突触, 局部场电位, 海马

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