中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (23): 6122-6133.doi: 10.12307/2026.355

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

胰高血糖素样肽1受体激动剂替西帕肽治疗阿尔茨海默病的潜在靶点

张晓敏，杜朋洋，张秀萍，薛国芳   

  1. 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:2025-07-26 接受日期:2025-08-27 出版日期:2026-08-18 发布日期:2026-01-05
  • 通讯作者: 张晓敏，硕士，主治医师，山西医科大学第二医院神经内科，山西省太原市 030001
  • 作者简介:张晓敏，女，1985年生，山西省太原市人，汉族，2013年山西医科大学毕业，硕士，主治医师，主要从事神经退行性疾病、脑血管疾病的机制和临床研究。 共同第一作者：杜朋洋，女，2001年生，山西省运城市人，汉族，山西医科大学在读硕士，主要从事神经退行性疾病的机制研究。
  • 基金资助:
    山西省高等教育“百亿工程”科技引导专项、煤炭环境致病与防治教育部重点实验室(BY-ZB-2024012)，项目负责人：薛国芳；山西省基础研究自然科学研究面上项目(202303021211213)，项目负责人：薛国芳

Potential targets of glucagon-like peptide 1 receptor agonist ticagrelor in the treatment of Alzheimer’s disease

Zhang Xiaomin, Du Pengyang, Zhang Xiuping, Xue Guofang   

  1. Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
    Zhang Xiaomin, MS, Attending physician, Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • Received:2025-07-26 Accepted:2025-08-27 Online:2026-08-18 Published:2026-01-05
  • Contact: Zhang Xiaomin, Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • About author:Du Pengyang, MS candidate, Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China Zhang Xiaomin and Du Pengyang contributed equally to this work.
  • Supported by:
    Shanxi Province Higher Education "Billion Project" Science and Technology Guidance Project, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, No. BY-ZB-2024012 (to XGF); Natural Science Research Project of Shanxi Province Basic Research, No. 202303021211213 (to XGF)

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摘要：



文题释义：
阿尔茨海默病：是一种中枢神经系统的退行性病变，主要发生在老年或老年前期。疾病的主要特征包括进行性的认知功能障碍和行为损害，其命名来源于首次描述这种疾病的德国医生阿尔茨海默。
血管紧张素Ⅱ2型受体(angiotensin II type 2 receptor，AGTR2)：属于G蛋白偶联受体家族成员，其作用包括：抑制细胞生长和胎儿组织发育，调节细胞外基质、神经元再生、细胞分化和凋亡，也可能有血管舒张作用。

背景：胰高血糖素样肽1受体激动剂作为神经退行性疾病治疗的新型候选药物，已在阿尔茨海默病临床研究中取得突破性进展，其中索马鲁肽等药物已推进至Ⅲ期临床试验阶段。然而，目前对于该类药物神经保护效应的分子作用机制仍存在显著的知识缺口。
目的：创新性地整合多组学分析技术与网络药理学方法，系统解析阿尔茨海默病病理相关基因谱系与替西帕肽潜在作用靶点的交集网络，鉴定关键调控基因，并通过体内外实验验证其分子机制。
方法：采用多维度研究策略：①基于DisGeNET数据库(整合了多种疾病相关的基因组学数据库)构建阿尔茨海默病差异表达基因谱。②通过PubChem数据库(小分子生物活性数据库)获取替西帕肽结构并筛选潜在靶点。③应用DAVID数据库开展GO功能注释及KEGG通路富集分析。④结合STRING数据库与Cytoscape 3.9.1构建蛋白质互作网络，经拓扑网络分析筛选关键基因。⑤细胞水平验证：将HT22细胞分为对照组、模型组(β-淀粉样蛋白1-42寡聚体处理36 h建立HT22细胞阿尔茨海默病体外模型)、给药组(先以β-淀粉样蛋白1-42寡聚体预处理24 h，再加入替西帕肽共处理12 h)，通过Western blot分析血管紧张素Ⅱ2型受体蛋白表达，ELISA检测突触蛋白1、突触后致密物质95等突触功能标志物表达水平。⑥动物实验验证：实验分为3组，对照组为WT型C57BL/6小鼠，腹腔注射生理盐水；模型组为3xTg小鼠(拟阿尔茨海默症小鼠)，腹腔注射生理盐水；给药组为3xTg小鼠，腹腔注射20 nmol/L替西帕肽；均为隔日1次，共给药15次。使用水迷宫技术分析阿尔茨海默病模型小鼠的认知行为学改善；使用Western blot定量分析β-淀粉样蛋白(6E10)、磷酸化的Tau蛋白(P-tau-181)的表达情况。
结果与结论：①从DisGeNET数据库筛选出阿尔茨海默病相关联的基因，共得到3 397个关联基因；根据蛋白关联度筛选出了10个连接度最高的关键基因：AGTR2、NTSR1、NTSR2、GHSR、C5AR1、C3AR1、OPRM1、SSTR2、OPRD1、STAT3；GO富集分析和KEGG通路分析，提示替西帕肽可能通过改善神经受体-配体功能来改善阿尔茨海默病。②细胞实验提示，替西帕肽可能通过改善阿尔茨海默病的突触功能来发挥治疗作用，血管紧张素Ⅱ2型受体可能是替西帕肽治疗阿尔茨海默病的潜在靶点。③动物实验提示，替西帕肽能够改善3xTg小鼠的认知能力，改善3xTg小鼠模型脑内的异常β-淀粉样蛋白沉积和Tau蛋白磷酸化。④结论：揭示血管紧张素Ⅱ2型受体是替西帕肽作用于阿尔茨海默病病理进程的关键分子靶点，替西帕肽可能通过调控血管紧张素Ⅱ2型受体介导的突触功能改善来治疗阿尔茨海默病。

https://orcid.org/0009-0003-4781-2110 (张晓敏)；https://orcid.org/0009-0006-6866-0760 (杜朋洋)


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: 替西帕肽, 阿尔茨海默病, 网络药理学, 血管紧张素Ⅱ2型受体, 蛋白互作网络, 突触功能

Abstract: BACKGROUND: Glucagon-like peptide 1 receptor agonists, as novel drug candidates for the treatment of neurodegenerative diseases, have achieved breakthrough progress in clinical research on Alzheimer’s disease, with drugs such as Semaglutide advancing to phase III clinical trials. However, there remains a significant knowledge gap regarding the molecular mechanism of neuroprotective effects of these drugs.
OBJECTIVE: To innovatively integrate multi-omics analysis techniques and network pharmacology methods, to systematically analyze the intersection network between the gene lineage related to Alzheimer’s disease pathology and the potential targets of ticagrelor, to identify key regulatory genes, and to verify their molecular mechanisms through in vitro and in vivo experiments.
METHODS: A multi-dimensional research strategy was adopted: (1) Constructing the differential expression gene profile of Alzheimer’s disease using the DisGeNET database that covers various disease-related genomics. (2) Obtaining the structure of Tirzepatide from PubChem database with bioactive molecules and screening potential targets. (3) Conducting Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using the DAVID database. (4) Constructing a protein-protein interaction network by combining the STRING database with Cytoscape 3.9.1, and screening key genes through topological network analysis. (5) Cell level verification: HT22 cells were divided into control group, and model group in which treatment with β-amyloid 1-42 oligomers for 36 hours was performed to develop an Alzheimer’s disease in vitro model in HT22 cells, and drug administration group in which the cells were pretreated with β-amyloid 1-42 oligomers for 24 hours, followed by co-treatment with ticrepotide for 12 hours. The expression of angiotensin II type 2 receptor protein was analyzed by western blot assay, and the expression levels of synaptic function markers such as synapse protein 1 and postsynaptic dense substance 95 were detected by ELISA. (6) Animal experiment verification: The experiment was divided into three groups. The control group, consisting of WT-type C57BL/6 mice, received intraperitoneal injection of physiological saline; the model group, consisting of 3xTg mice that were Alzheimer’s disease-mimicking mice, received intraperitoneal injection of physiological saline; and the drug administration group, consisting of 3xTg mice, received intraperitoneal injection of 20 nmol/L ticrepotide. All treatments were administered once every other day for a total of 15 times. The cognitive behavior improvement in the Alzheimer’s disease mouse model was analyzed using the water maze technique; the expression of β-amyloid (6E10) and phosphorylated Tau protein (P-tau-181) was quantitatively analyzed by western blot assay.
RESULTS AND CONCLUSION: (1) A total of 3 397 genes associated with Alzheimer's disease were screened from the DisGeNET database. Based on protein connectivity, 10 key genes with the highest connectivity were identified: AGTR2, NTSR1, NTSR2, GHSR, C5AR1, C3AR1, OPRM1, SSTR2, OPRD1, and STAT3. GO enrichment analysis and KEGG pathway analysis suggested that ticagrelor may improve Alzheimer’s disease by enhancing neuroreceptor-ligand function. (2) Cell experiments suggested that ticagrelor may exert therapeutic effects by improving synaptic function in Alzheimer’s disease. The angiotensin II type 2 receptor may be a potential target for Ticagrelor in the treatment of Alzheimer’s disease. (3) Animal experiments indicated that ticagrelor can improve cognitive ability in 3xTg mice and alleviate abnormal β-amyloid deposition and tau protein phosphorylation in the brains of 3xTg mouse models. To conclude, the angiotensin II type 2 receptor is revealed as a key molecular target for ticagrelor in the pathological process of Alzheimer's disease. Ticagrelor may treat Alzheimer's disease by regulating synaptic function mediated by the angiotensin II type 2 receptor.


Key words: tirzepatide, Alzheimer’s disease, network pharmacology, angiotensin II type 2 receptor, protein-protein interaction network, synaptic function

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