胰高血糖素样肽1类似物对阿尔兹海默症的神经保护作用及机制研究进展

doi:10.12300/j.issn.1674-5817.2022.136

实验动物与比较医学 ›› 2023, Vol. 43 ›› Issue (2): 186-193.DOI: 10.12300/j.issn.1674-5817.2022.136

胰高血糖素样肽1类似物对阿尔兹海默症的神经保护作用及机制研究进展

梅承翰(), 陈蓓蓓()()

贵州省分析测试研究院, 贵阳 550000

收稿日期:2022-08-30 修回日期:2022-12-09 出版日期:2023-04-25 发布日期:2023-05-16
通讯作者: 陈蓓蓓（1979—），女，博士，副研究员，从事材料学、健康毒理学相关工作。E-mail： chenbeibei@gzata.cn。ORCID：0009-0001-1609-2259
作者简介:梅承翰（1991—），男，博士研究生，工程师，从事血脑屏障破坏在神经退行性和血管性疾病中的生理作用及分子调控机制研究。E-mail： ckklmch@sina.cn
基金资助:
贵州科学院省级科研专项资金项目“食用菌多糖提取物的增强免疫力功能评价研究”(黔科院科专合字〔2020〕02号);贵州科学院创新人才团队能力提升工程建设项目“贵州特色优势资源功效性评价及产品研发团队”

Research Progress on Neuroprotective Effects and Mechanisms of Glucagon-like Peptide 1 Analogues in Alzheimer's Disease

Chenghan MEI(), Beibei CHEN()()

Guizhou Academy of Testing and Analysis, Guiyang 550000, China

Received:2022-08-30 Revised:2022-12-09 Published:2023-04-25 Online:2023-05-16
Contact: CHEN Beibei (ORCID: 0009-0001-1609-2259 ), E-mail: chenbeibei@gzata.cn

摘要/Abstract

摘要：

胰高血糖素样肽1（glucagon-like peptide 1，GLP-1）是一种由肠道分泌的促胰岛素激素，能有效增强胰岛素的释放，同时还具有多种药理活性。GLP-1类似物已广泛用于治疗Ⅱ型糖尿病。而阿尔兹海默症（Alzheimer's disease，AD）与Ⅱ型糖尿病之间存在胰岛素抵抗等共同的病理特征，并且流行病学调查研究显示Ⅱ型糖尿病会显著增加AD发病风险，二者紧密相关。目前，GLP-1类似物在AD临床前动物研究和人体临床试验中均显示出一定的治疗效果。本文首先介绍了GLP-1和AD的主要特征，然后分析了临床前动物模型研究中GLP-1治疗AD的几种作用机制。GLP-1易于透过血脑屏障，通过结合并激活脑中广泛分布的GLP-1受体（glucagon-like peptide 1 receptor，GLP-1R）影响多个病理生理过程，如葡萄糖代谢、神经炎症、线粒体功能和细胞增殖等。而胰岛素抵抗和炎症是AD与Ⅱ型糖尿病的关键共同通路。GLP-1可能是通过改善线粒体功能和糖酵解、降低氧化应激水平、抗炎、抗凋亡、诱导神经发生和抑制胶质细胞增生等，发挥神经保护作用。本文希望为进一步研究GLP-1类似物对AD的治疗作用提供参考，并为AD患者提供新的治疗策略。

关键词: 胰高血糖素样肽1, 阿尔兹海默症, β-淀粉样蛋白, 神经保护作用

Abstract:

Glucagon-like peptide 1 (GLP-1) is a kind of incretin produced in the intestinal with multiple pharmacological effects, which can stimulate insulin secretion effectively. Various GLP-1 analogues have been widely used in the treatment of type 2 diabetes mellitus. Alzheimer's disease (AD) is closely related to type 2 diabetes mellitus, with some common pathological features, such as insulin resistance, and epidemiological studies also showed that patients with type 2 diabetes mellitus have an increased risk of developing AD. GLP-1 analogues have shown beneficial effects in both preclinical animal research and clinical trials of AD. Therefore, the authors summarized the main characteristics of GLP-1 and AD, and analyzed the mechanisms of GLP-1 in preclinical AD studies of animal models. GLP-1 readily crosses the blood-brain barrier and exerts its neuroprotective effects by binding to and activating the widely distributed GLP-1 receptors (GLP-1Rs) in the brain, affecting multiple physiological and pathological processes including glucose metabolism, neuroinflammation, mitochondrial function, and cell proliferation. Insulin resistance and inflammation are key common pathways in AD and type 2 diabetes. GLP-1 may exert its neuroprotective effects by improving mitochondrial function and glycolysis, reducing oxidative stress levels, exerting anti-inflammatory and anti-apoptotic effects, inducing neurogenesis, and inhibiting glial cell proliferation. This paper maybe provide the reference for further study of GLP-1 analogues in AD, hoping to open new therapy venues for AD patients.

Key words: Glucagon-like peptide 1, Alzheimer's disease, Amyloid β-protein, Neuroprotective effect

中图分类号:

R-332

梅承翰, 陈蓓蓓. 胰高血糖素样肽1类似物对阿尔兹海默症的神经保护作用及机制研究进展[J]. 实验动物与比较医学, 2023, 43(2): 186-193.

Chenghan MEI, Beibei CHEN. Research Progress on Neuroprotective Effects and Mechanisms of Glucagon-like Peptide 1 Analogues in Alzheimer's Disease[J]. Laboratory Animal and Comparative Medicine, 2023, 43(2): 186-193.

图/表 2

参考文献 44

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药物 Drug	动物 Animal	给药前月龄或体质量 Age or body mass before dosing	给药方式及剂量 Dosage and Administration	给药周期 Dosing intervals	行为学实验 Behavioural experiments	结论 Conclusions
利拉鲁肽 Liraglutide^[3]	APP/PS1小鼠（♂）	14月龄	ip，25 nmol/kg体质量	qd，连续2月	新物体识别、水迷宫	逆转记忆损害
利拉鲁肽 Liraglutide^[4]	5xFAD小鼠（♂）	4月龄	ih，25 nmol/kg体质量	qd，连续2月	水迷宫	改善认知
GLP-1/GIP/Gcg triagonist^[5]	3xTg-AD小鼠（♂/♀）	7月龄	ip，10 nmol/kg体质量	qd，连续30 d	旷场、Y迷宫、水迷宫	改善长期空间记忆和工作记忆
GLP-1/GIP dual agonist DA5-CH^[6]	APP/PS1小鼠（♂/♀）	9月龄	ip，10 nmol/kg体质量	qd，连续28 d	旷场、Y迷宫、水迷宫	改善工作记忆和长期空间记忆
利拉鲁肽 Liraglutide^[7]	Swiss小鼠（脑室内注射Aβ寡聚物，♂）	3月龄	ip，25 nmol/kg体质量	qd，连续7 d	新物体识别、对象位置记忆模型	可逆转Aβ寡聚物引起的记忆障碍
艾塞那肽Exendin-4^[8]	SD大鼠（海马内微量注射Aβ1–42，♂）	220~260 g	海马内微量注射， 0.2 nmol（1 µL）	单次	水迷宫	显著拮抗Aβ片段引起的空间学习和记忆能力损害
GLP-1/GIP dual agonist DA4-JC^[9]	3xTg-AD小鼠（♂/♀）	8月龄	ip，10 nmol/kg体质量	qd，连续46 d	旷场、新物体识别、Y迷宫、水迷宫	改善认知

药物 Drug	动物 Animal	给药前月龄或体质量 Age or body mass before dosing	给药方式及剂量 Dosage and Administration	给药周期 Dosing intervals	行为学实验 Behavioural experiments	结论 Conclusions
利拉鲁肽 Liraglutide^[3]	APP/PS1小鼠（♂）	14月龄	ip，25 nmol/kg体质量	qd，连续2月	新物体识别、水迷宫	逆转记忆损害
利拉鲁肽 Liraglutide^[4]	5xFAD小鼠（♂）	4月龄	ih，25 nmol/kg体质量	qd，连续2月	水迷宫	改善认知
GLP-1/GIP/Gcg triagonist^[5]	3xTg-AD小鼠（♂/♀）	7月龄	ip，10 nmol/kg体质量	qd，连续30 d	旷场、Y迷宫、水迷宫	改善长期空间记忆和工作记忆
GLP-1/GIP dual agonist DA5-CH^[6]	APP/PS1小鼠（♂/♀）	9月龄	ip，10 nmol/kg体质量	qd，连续28 d	旷场、Y迷宫、水迷宫	改善工作记忆和长期空间记忆
利拉鲁肽 Liraglutide^[7]	Swiss小鼠（脑室内注射Aβ寡聚物，♂）	3月龄	ip，25 nmol/kg体质量	qd，连续7 d	新物体识别、对象位置记忆模型	可逆转Aβ寡聚物引起的记忆障碍
艾塞那肽Exendin-4^[8]	SD大鼠（海马内微量注射Aβ1–42，♂）	220~260 g	海马内微量注射， 0.2 nmol（1 µL）	单次	水迷宫	显著拮抗Aβ片段引起的空间学习和记忆能力损害
GLP-1/GIP dual agonist DA4-JC^[9]	3xTg-AD小鼠（♂/♀）	8月龄	ip，10 nmol/kg体质量	qd，连续46 d	旷场、新物体识别、Y迷宫、水迷宫	改善认知

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胰高血糖素样肽1类似物对阿尔兹海默症的神经保护作用及机制研究进展

Research Progress on Neuroprotective Effects and Mechanisms of Glucagon-like Peptide 1 Analogues in Alzheimer's Disease

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