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

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。

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.