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

doi:10.12300/j.issn.1674-5817.2022.136

Abstract

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

CLC Number:

R-332

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. DOI: 10.12300/j.issn.1674-5817.2022.136.

Figures/Tables 2

References 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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