利拉鲁肽对2型糖尿病阿尔茨海默病样三重转基因小鼠学习记忆的影响  

The effects of liraglutide on learning and memory in Alzheimer-like triple transgenic mice with type 2 diabetes

作　　者：孙洁[1] 陈书仪 路素素 郑军[1] 邓艳秋[1] 

机构地区：[1]天津医科大学基础医学院生理学与病理生理学教研室,300070

出　　处：《天津医药》2015年第7期728-732,共5页Tianjin Medical Journal

基　　金：国家自然科学基金资助项目(81270422)

摘　　要：目的研究2型糖尿病(T2DM)对阿尔茨海默病(AD)样APP/PS1/Tau三重转基因(3×Tg)小鼠学习记忆能力的影响和利拉鲁肽(LIR)对此模型神经保护作用的相关机制。方法将1月龄C57BL/6小鼠设为正常对照(WT)组,1月龄3×Tg小鼠分为对照(Tg)组、单纯利拉鲁肽(Tg+LIR)组、Tg+T2DM组、T2DM+利拉鲁肽(Tg+T2DM+LIR)组。T2DM造模方法为喂2个月高脂高糖饲料,然后腹腔注射链脲佐菌素(STZ),空腹血糖大于7 mmol/L为造模成功,腹腔注射LIR治疗2个月。5月龄时测体质量、空腹血糖。Morris水迷宫检测空间学习记忆能力,Western blot-ting检测Tau、神经丝(NFs)和胰岛素受体底物(IRS)磷酸化水平。ELISA检测转入的人APP基因表达的人β淀粉样蛋白(Aβ)42,检测LIR对Aβ的影响。结果与Tg组比较,Tg+T2DM组小鼠质量、空腹血糖、逃避潜伏期、p T231、p T181、SMI31、Aβ42增加,穿越隐匿平台次数及p IRS减少。LIR能减轻高脂高糖饮食及T2DM造成的体质量和血糖的增加,能缓解T2DM对3×Tg小鼠空间学习记忆能力的损伤,改善T2DM对3×Tg小鼠Tau、NFs及IRS蛋白磷酸化的影响,减少3×Tg小鼠的Aβ沉积。结论 T2DM会加重3×Tg小鼠的AD样症状,而LIR对其有保护作用。Objective To investigate the effects of type 2 diabetes on learning and memory of APP/PS1/Tau tripletransgenic（3×Tg） mice of Alzheimer＇s disease, and the protective mechanism of liraglutide（LIR） thereof. Methods Onemonth old C57BL/6 mice were set to be control group（WT）. One month old 3×Tg mice were divided into control group（Tg）,liraglutide group（Tg＋LIR）, type 2 diabetes group（Tg＋T2DM） and liraglutide treatment group（Tg＋T2DM＋LIR）. The modelof T2 DM was established by feeding the high fat and sugar fodder, and then injecting streptozotocin（STZ） in mice, makingsure the fasting blood glucose was more than 7 mmol/L. Then the subcutaneous injection of LIR was administered for 2months. The values of body weight and fasting blood glucose were detected at age of 5-month. Morris water maze was appliedto evaluate the spatial learning and memory ability. Western blotting assay was used to measure the levels of phosphorylatedTau, neurofilament（NFs） and insulin receptor substrates. ELISA was used to detect the human Aβ 42 to evaluate the effectof LIR on-amyloid. Results LIR can reduce body weight and blood glucose, can alleviate spatial learning and memorydamaging caused by T2 DM, and also can improve phosphorylated Tau levels, NFs and insulin receptor substrates caused byT2 DM, and finally can reduce the deposition of β-amyloid of 3×Tg mice. Conclusion T2 DM can aggravate symptoms ofAD in 3×Tg mice, and LIR has a protective effect on it.

关 键 词：阿尔茨海默病 糖尿病 2型 淀粉样Β蛋白 胰岛素抵抗 利拉鲁肽 TAU 胰岛素受体底物 神经丝 

分 类 号：R742[医药卫生—神经病学与精神病学]