中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (34): 8962-8969.doi: 10.12307/2026.897

• 组织构建实验造模 experimental modeling in tissue construction • 上一篇    下一篇

玛仕度肽改善APP/PS1/Tau三转基因小鼠的认知能力

袁晶晶1，张晓敏2，杜朋洋2，王维峰1   

  1. 1山西省针灸医院脑病一科，山西省太原市  030001；2山西医科大学第二医院神经内科，山西省太原市  030001

  • 收稿日期:2025-10-15 修回日期:2026-02-28 出版日期:2026-12-08 发布日期:2026-04-14
  • 通讯作者: 王维峰，主任医师，山西省针灸医院脑病一科，山西省太原市 030001
  • 作者简介:袁晶晶，女，1986年生，山西省太原市人，汉族，2014年山西医科大学毕业，硕士，主治医师，主要从事脑血管疾病的机制和临床研究以及神经变性疾病的机制和临床研究。
  • 基金资助:
    山西省中医药管理局项目(024ZYY2B014)，项目负责人：袁晶晶；山西中医药大学2020年度山西教育厅项目
    (2020L0436)，项目负责人：袁晶晶；山西省教育厅项目(2022L156)，项目负责人：张晓敏

Mazdutide improves cognitive function in APP/PS1/Tau triple transgenic mice

Yuan Jingjing1, Zhang Xiaomin2, Du Pengyang2, Wang Weifeng1   

  1. 1Department of Cerebral Diseases I, Shanxi Provincial Hospital of Acupuncture and Moxibustion, Taiyuan 030001, Shanxi Province, China; 2Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • Received:2025-10-15 Revised:2026-02-28 Online:2026-12-08 Published:2026-04-14
  • Contact: Wang Weifeng, Chief physician, Department of Cerebral Diseases I, Shanxi Provincial Hospital of Acupuncture and Moxibustion, Taiyuan 030001, Shanxi Province, China
  • About author:Yuan Jingjing, MS, Attending physician, Department of Cerebral Diseases I, Shanxi Provincial Hospital of Acupuncture and Moxibustion, Taiyuan 030001, Shanxi Province, China
  • Supported by:
    Shanxi Provincial Administration of Traditional Chinese Medicine, No. 024ZYY2B014 (to YJJ); Shanxi Provincial Department of Education Project for Shanxi University of Chinese Medicine in 2020, No. 2020L0436 (to YJJ); Shanxi Provincial Department of Education Project, No. 2022L156 (to ZXM)

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摘要：


文题释义：
阿尔茨海默病：为一种起病隐匿的神经退行性疾病，是痴呆症最常见的形式。其核心病理特征表现为大脑内β-淀粉样蛋白异常沉积形成斑块和Tau蛋白过度磷酸化导致神经纤维缠结，引发神经元大量丢失和突触功能损伤。患者临床表现为进行性记忆减退、认知功能障碍、行为异常乃至丧失生活自理能力，给患者家庭及社会带来沉重负担。目前尚无能够逆转或治愈该病的药物，现有疗法仅能暂时缓解部分症状，开发能干预疾病根本进程的新疗法是全球面临的巨大挑战。
玛仕度肽：一种正处于研究阶段的新型双靶点激动剂，它可同时激活人体内的胰高血糖素样肽1受体和胰高血糖素受体，该药物最初因其在临床研究中展现出的强效降糖和减重效果而备受关注。此次研究将玛仕度肽的研究领域拓展至神经退行性疾病，创新性地提出其可能成为治疗阿尔茨海默病的潜在新策略，其作用机制可能远超简单的代谢调控，包括通过“肠-脑轴”抑制神经炎症、改善脑内能量代谢、促进神经营养因子分泌，以及此次研究所揭示的通过抑制内皮素受体A(EDNRA)来改善脑血管功能和减轻β-淀粉样蛋白、Tau病理负荷，从而多维度改善认知功能，代表了阿尔茨海默病治疗药物开发的一个新方向。

背景：阿尔茨海默病的病理进程与β-淀粉样蛋白/Tau沉积及脑血管功能障碍密切相关，现有疗法难以有效干预。近年来胰高血糖素样肽1受体激动剂治疗阿尔茨海默病的相关研究趋向热门，玛仕度肽(Mazdutide)作为新型胰高血糖素样肽1受体/胰高血糖素受体双激动剂，其阿尔茨海默病治疗机制尚未阐明。
目的：采用网络药理学与实验验证相结合的策略，系统性探究玛仕度肽改善阿尔茨海默病认知功能的作用机制，并筛选其潜在的核心分子靶点，为开发该疾病的新治疗策略提供理论依据。
方法：采用多组学整合策略，基于DisGeNET和SEA数据库筛选阿尔茨海默病-玛仕度肽共定位靶点；通过STRING构建蛋白互作网络，Cytoscape拓扑分析鉴定核心枢纽基因；在APP/PS1/Tau三转基因阿尔茨海默病小鼠模型中，腹腔注射玛仕度肽(30 nmol/kg)，结合Morris水迷宫、新物体识别、Y迷宫评估认知功能，Western blot检测海马β-淀粉样蛋白(6E10)、p-Tau181及内皮素受体A的表达。  
结果与结论：①筛选出52个共定位靶点，内皮素受体A为排名第一的枢纽基因；②玛仕度肽可显著改善3xTg小鼠认知：空间记忆潜伏期缩短、情景记忆识别指数提升、工作记忆自发交替正确率增加、同步降低海马病理负荷，p-Tau181下降，内皮素受体A过表达下降；③基因本体论/京都基因与基因组百科全书富集揭示核心通路：在生物过程中，最显著富集的条目包括血压调节、胺类转运调控以及胺类物质转运；细胞组分分析结果表明，对称突触、精子头部和伪足结构是主要的富集位点；分子功能方面，G蛋白偶联肽受体活性、肽受体活性及神经肽受体活性占据主导地位；京都基因与基因组百科全书通路分析中，神经活性配体-受体相互作用、钙信号通路和激素信号传导为最显著的3大通路；④此次研究证实玛仕度肽可能通过靶向抑制内皮素受体A过表达，减轻神经元病理损伤，多维度逆转阿尔茨海默病认知缺陷；内皮素受体A的发现为阿尔茨海默病提供了全新的治疗靶点。 

https://orcid.org/0009-0007-4859-8856(袁晶晶)


中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 阿尔茨海默病, 玛仕度肽, 网络药理学, 内皮素受体A, 生物信息学

Abstract: BACKGROUND: The pathological process of Alzheimer's disease is closely related to β-amyloid/Tau deposition and cerebrovascular dysfunction, and existing therapies are difficult to effectively intervene. In recent years, research on glucagon-like peptide-1 receptor agonists for the treatment of Alzheimer's disease has gained increasing popularity. As a novel dual agonist of the glucagon-like peptide-1 receptor and glucagon receptor, the therapeutic mechanism of Mazdutide in Alzheimer’s disease remains to be elucidated.  
OBJECTIVE: To systematically explore the mechanism by which Mazdutide improves cognitive function in Alzheimer’s disease using a strategy combining network pharmacology and experimental validation, and to identify its potential core molecular targets, providing a theoretical basis for developing new treatment strategies for this disease.  
METHODS: A multi-omics integration strategy was employed: Alzheimer’s disease-Mazdutide co-localization targets were screened based on the DisGeNET and SEA databases; protein-protein interaction networks were constructed via STRING, and core hub genes were identified through Cytoscape topology analysis; in APP/PS1/Tau triple transgenic Alzheimer’s disease mice, cognitive function was assessed following intraperitoneal injection of mazdutide (30 nmol/kg) using the Morris water maze, novel object recognition, and Y-maze tests. Western blot was used to detect hippocampal Aβ (6E10), p-Tau181, and endothelin receptor A expression.  
RESULTS AND CONCLUSION: (1) Fifty-two co-localized targets were identified, with endothelin receptor A ranking as the top hub gene. (2) Mazdutide significantly improved cognition in 3xTg mice: spatial memory latency was shortened, episodic memory recognition index was enhanced, spontaneous alternation accuracy in working memory was increased, hippocampal pathological load was reduced, p-Tau181 levels were decreased, and EDNRA overexpression was suppressed. (3) Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed core pathways: in biological processes, the most significantly enriched terms included regulation of blood pressure and regulation of amine transport; cellular component analysis showed primary enrichment in symmetric synapses, sperm head, and pseudopodium structures; in molecular function, G protein-coupled peptide receptor activity, peptide receptor activity, and neuropeptide receptor activity dominated; in Kyoto Encyclopedia of Genes and Genomes pathway analysis, neuroactive ligand-receptor interaction, calcium signaling pathway, and hormone signaling were the three most significant pathways. (4) This study confirmed that Mazdutide may alleviate neuronal pathological damage and multi-dimensionally reverse cognitive impairment in Alzheimer’s disease by targeting and inhibiting EDNRA overexpression. The discovery of EDNRA provides a novel therapeutic target for Alzheimer’s disease.  

Key words: Alzheimer’s disease, Mazdutide, network pharmacology, endothelin receptor A, bioinformatics

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