胰高血糖素样肽1(GLP-1)改善阿尔茨海默病大鼠模型的认知功能及其机制研究

The effect and mechanism of Glucagon like peptide 1(GLP-1) in improving cognitive function of Alzheimer's disease rat model

目的探讨胰高血糖素样肽1(GLP-1)改善阿尔茨海默病大鼠认知功能的机制。方法以正常成年雄性SD大鼠为研究对象,将其随机分为正常对照组、AD模型组、AD模型+GLP-1干预组和AD模型+PPARγ抑制剂+GLP-1干预组;其中AD模型组以侧脑室注射STZ(3 mg/kg,10μL)制造AD模型,AD模型+GLP-1干预组在AD造模基础上每日腹腔注射利拉鲁肽(200μg/kg,10μL),连续给药28 d,AD模型+PPARγ抑制剂+GLP-1干预组在AD造模基础上侧脑室注射PPARγ抑制剂GW9662(2.5 nmol/g,10μL),随后腹腔注射利拉鲁肽(200μg/kg,10μL)并连续给药28 d;观察4组大鼠在Morris水迷宫中的学习和记忆能力变化;ELISA方法观察各组大鼠海马Aβ42的水平;Western blot观察各组大鼠海马PPARγ蛋白表达水平。结果与AD模型组比较,GLP-1干预后的AD大鼠在Morris水迷宫中学习和记忆能力明显改善,海马Aβ42的水平显著降低,海马PPARγ蛋白表达水平显著升高(P<0.05);与AD模型+GLP-1干预组比较,AD模型+PPARγ抑制剂+GLP-1干预组大鼠海马PPARγ蛋白表达水平显著降低,在Morris水迷宫中学习和记忆能力明显下降,海马Aβ42的水平显著增高(P<0.05)。结论 GLP-1可能通过激活PPARγ抑制Aβ蓄积,从而起到改善阿尔茨海默病的认知功能作用。

Objective To explore the mechanism of glucagon like peptide 1(GLP-1)in improving cognitive function of Alzheimer's disease rat model.Methods The health adult male SD rats were randomly divided into four groups,which were normal control group,AD model group,AD model+GLP-1 group,and AD model+PPARγinhibitor+GLP-1 group.The AD model rats were made by injection of STZ(3 mg/kg,10μL)in the lateral ventricle.The rats of AD model+GLP-1 group were made by intraperitoneal injected Liraglutide(200μg/kg,10μL)on the basis of AD model for 28 days.The rats of AD model+PPARγinhibitor+GLP-1 group were made by injected PPARγinhibitor GW9662(2.5 nmol/g,10μL)into the lateral ventricle on the basis of AD model and then intraperitoneal injected Liraglutide(200μg/kg,10μL)for 28 days.The learning and memory ability of each group in the Morris water maze were observed.The level of Aβ42in the hippocampus of each group was observed by ELISA.And the PPARγprotein expression level in the hippocampus of each group was observed by Western blot.Results Compared with the AD model group,the learning and memory ability of AD rats was significantly improved,and the level of Aβ42 in the hippocampus decreased significantly,and the expression level of PPARγprotein in the hippocampus was significantly increased in AD model+GLP-1 group.Compared with the AD model+GLP-1 group,the expression level of PPARγprotein in the hippocampus was significantly decreased,and the learning and memory ability decreased significantly,and the level of Aβ42in the hippocampus increased significantly in the AD model+PPARγinhibitor+GLP-1 group.Conclusion GLP-1 might inhibit the accumulation of Aβby activating PPARγ,and improve the cognitive function of Alzheimer's disease.