索马鲁肽对转基因APP/PS1/tau阿尔茨海默病小鼠认知功能的影响  

Effects of Semaglutide on cognitive function in transgenic APP/PS1/tau mice

作　　者：程雨菲 马义鹏 陈晨 刘虹 CHENG Yufei;MA Yipeng;CHEN Chen;LIU Hong(School of Public Health,Shanxi Medical University,Taiyuan 030001,China;Department of Neurology,Shanxi Cardiovascular Hospital)

机构地区：[1]山西医科大学公共卫生学院,太原030001 [2]山西省心血管病医院神经内科

出　　处：《山西医科大学学报》2024年第7期879-884,共6页Journal of Shanxi Medical University

基　　金：山西省“四个一批”科技兴医创新资助项目(2022XM07);山西省心血管病医院科研激励计划项目(XYS20180203)。

摘　　要：目的探究索马鲁肽能否有效改善阿尔茨海默病(AD)转基因APP/PS1/tau小鼠的认知功能。方法本研究选用的AD模型小鼠是含有PS1M146V、APPSwe和tauP301L 3个基因突变位点的APP/PS1/tau三重转基因AD小鼠(3×Tg-AD)。7月龄的APP/PS1/tau三重转基因小鼠及同窝非转基因野生型(wild type,WT)C57BL/6小鼠分别随机分为:AD模型组(Tg)和索马鲁肽组(Tg+Semaglutide)、正常对照组(WT)和索马鲁肽对照组(WT+Semaglutide)。WT+Semaglutide组和Tg+Semaglutide组腹腔注射索马鲁肽,WT组和Tg组腹腔注射等量生理盐水,小鼠干预30次,每2 d干预一次。干预结束后进行新物体识别实验研究小鼠认知功能的改变,行ELISA实验检测小鼠血清中与认知相关的标志物Aβ_(1-42)的水平,采用Western blot法检测小鼠海马区Ser231位点磷酸化的Tau蛋白表达。结果新物体识别实验中,与Tg组相比,Tg+Semaglutide组新物体分辨率更高(P<0.05);与WT组相比,WT+Semaglutide组分辨率更高(P<0.05)。干预结束后(9月龄),各组间小鼠体质量及血糖浓度比较,差异无统计学意义(P>0.05)。蛋白质印迹法实验中,与Tg组相比,Tg+Semaglutide组Tau231磷酸化水平降低(P<0.05);与WT组相比,WT+Semaglutide组Tau231磷酸化水平也略降低,但组间差异无统计学意义。酶联免疫吸附法实验中,与Tg组相比,Tg+Semaglutide组Aβ_(1-42)浓度降低(P<0.05);与WT组相比,WT+Semaglutide组Aβ_(1-42)浓度也降低(P<0.05)。结论索马鲁肽可降低AD小鼠血清中与认知相关的标志物Aβ_(1-42)水平和海马区Ser231位点磷酸化的Tau蛋白表达,能有效改善AD小鼠的认知功能,且索马鲁肽对小鼠体质量及血糖的影响在短时间里未见明显变化,安全性较高。Objective To explore whether Semaglutide can effectively improve the cognitive function of amyloid precursor protein(APP)/presenilin-1(PS1)/microtubule-associated protein tau(tau)transgenic mice with Alzheimer′s disease(AD).Methods AD model mice with three gene mutation sites,PS1M146V,APPSwe,and tauP301L,that is,APP/PS1/Tau triple transgenic AD mice(3×Tg-AD)were selected for this study.Seven-month-old APP/PS1/tau triple transgenic mice and non-transgenic wild type(WT)C57BL/6 littermates were respectively randomized into AD model group(Tg)and Semaglutide group(Tg+Semaglutide),and normal control group(WT)and Semaglutide control group(WT+Semaglutide).Mice in WT+Semaglutide group and Tg+Semaglutide group were intraperitoneally injected with Semaglutide,and mice in WT group and Tg group were intraperitoneally injected with equal amounts of normal saline.The intervention was performed once two days for 30 times.After the intervention,the novel object recognition test was conducted to study the changes in the cognitive function of mice.The enzyme-linked immunosorbent assay(ELISA)was conducted to detect the serum levels of cognition-related marker Aβ_(1-42) in mice.Western blot method was used to detect the expression of phosphorylated Tau protein at the Ser231 site in the hippocampus of mice.Results In novel object recognition test,the new object discrimination ratio in Tg+Semaglutide group was higher than that in Tg group(P<0.05),and the new object discrimination ratio in WT+Semaglutide group was higher than that in WT group(P<0.05).After the intervention(9 months old),there was no significant difference in body mass and blood glucose concentration among all groups(P>0.05).Western blot experiments showed that the phosphorylation level of Tau231 was lower in Tg+Semaglutide group than in Tg group(P<0.05),while the phosphorylation level of Tau231 was also slightly lower in WT+Semaglutide group than in WT group,but there was no significant difference between two groups.ELISA results showed that the concentration of Aβ

关 键 词：索马鲁肽 阿尔茨海默病 TAU蛋白磷酸化 APP/PS1/tau三转基因小鼠 Aβ_(1-42) 2型糖尿病 

分 类 号：R741[医药卫生—神经病学与精神病学]