雷帕霉素蛋白调控Homer3对阿尔茨海默病认知功能的影响  

Effect of mammalian target of rapamycin on cognitive dysfunction of Alzheimer′s Disease via regulating Homer3

作　　者：黄娅琴 刘孝国[2] 张玲[3] 於阳 薛娟 孙建良[2] Huang Yaqin;Liu Xiaoguo;Zhang Ling;Yu Yang;Xue Juan;Sun Jianliang(Department of Anesthesiology,Affiliated Hangzhou First People′s Hospital,Zhejiang University School of Medicine,Hangzhou 310006,China;Department of Anesthesiology,the Second Affiliated Hospital of Wenzhou Medical University,Wenzhou 325027,China;the Fourth Clinical College of Zhejiang Chinese Medical University,Hangzhou 310053,China)

机构地区：[1]浙江大学医学院附属杭州市第一人民医院麻醉科,杭州310006 [2]温州医科大学附属第二医院麻醉科,温州325027 [3]浙江中医药大学第四临床学院,杭州310053

出　　处：《中华医学杂志》2020年第17期1336-1340,共5页National Medical Journal of China

基　　金：浙江省自然基金项目(LY17C090002);杭州市科委社会发展计划项目(20170533B32);浙江省医药卫生科研项目(2017KY520)。

摘　　要：目的通过观察哺乳动物雷帕霉素靶蛋白(mTOR)对淀粉样蛋白β1-42(Aβ1-42)所致阿尔茨海默病(AD)小鼠海马Homer3的影响,探讨其对AD认知功能的影响。方法32只C57BL/6小鼠随机数字表法分为4组:Sham组(小鼠海马注射生理盐水)、AD组(小鼠海马注射Aβ1-42)、二甲基亚砜(DMSO)组(海马注射Aβ1-42制成AD后,小鼠腹腔注射溶剂DMSO连续14 d)、雷帕霉素(RAPA)组(海马注射Aβ1-42制成AD后,小鼠腹腔注射雷帕霉素1mg/kg连续14 d),每组8只。对每组小鼠进行Morris迷宫和Y迷宫实验,测定其认知功能,采用蛋白印迹方法检测各组小鼠海马Aβ1-42、mTOR、磷酸化mTOR(p-mTOR)、Homer3的表达量。结果与Sham组相比,AD组小鼠逃避潜伏期明显延长,目的象限停留时间缩短,穿环次数明显减少,交替率降低,差异均有统计学意义(均P<0.05);与DMSO组相比,RAPA组小鼠逃避潜伏期明显缩短,目的象限停留时间增加,穿环次数明显增加,交替率增加,差异均有统计学意义(均P<0.05)。与Sham组相比,AD组小鼠海马Aβ1-42、p-mTOR表达量明显增加,Homer3表达量减少,差异均有统计学意义(均P<0.05);与DMSO组相比,RAPA组小鼠海马Aβ1-42、p-mTOR表达量减少(P<0.05),Homer3表达量增加,差异均有统计学意义(均P<0.05)。结论mTOR抑制剂雷帕霉素可改善Aβ1-42所致AD小鼠行为认知功能障碍,减少脑内Aβ1-42沉积,其作用机制可能与抑制mTOR磷酸化、上调突触相关蛋白Homer3的表达有关。Objective To exploer the effect of mammalian target ofrapamycin(mTOR)on cognitive dysfunction of mice with Alzheimer′s disease(AD)induced by amyloidβ1-42(Aβ1-42)via observing the regulation effect of rapamycin on Homer3 in hippocampus.Methods The 32 mice were randomly divided into fourgroups:sham group(the hippocampus of mice was injected with normal saline);AD group(the hippocampus of mice was injected with Aβ1-42);DMSO group(AD mice induced by Aβ1-42 were intraperitoneally injected with dimethylsulfoxide for 14 days);RAPA group(AD mice induced by Aβ1-42 were intraperitoneally injected with rapamycin 1 mg/kg for 14 days).Morris maze and Y maze experiments to measuring cognitive function and immunowestern bloting detecting the expression of Aβ1-42,mTOR,p-mTOR and Homer3 in the hippocampus were conducted on each group of mice.Results Compared with sham group,the AD group showed significantly longer escape latency,shoter residence time of objective quadrant,less numbers of crossing of original platform,lower alternation ratio(P<0.05);Compared with DMSO group,RAPA group showed significantly shorter escape latency,longer residence time of objective quadrant,more numbers of crossing of original platform,more alternation ratio(P<0.05).The levels of Aβ1-42 and p-mTOR were increased,the levels of Homer3 were decreased in DMSO group mice′s hippocampus compared with sham group(P<0.05);the levels of Aβ1-42 and p-mTOR were decreased,the levels of Homer3 were increased in RAPA group mice′s hippocampus compared with DMSO group(P<0.05).Conclusion The inhibitor of mTOR rapamycin can improve the cognitive dysfunction of mice with AD induced by Aβ1-42 and reduce deposition of Aβ1-42 in the hippocampus,and the possible mechanism is rapamycin depressing the phosphorylation of mTOR as the same as Up-regulation the expression level of Homer3.

关 键 词：阿尔茨海默病 雷帕霉素 淀粉样蛋白β1-42 哺乳动物雷帕霉素蛋白 磷酸化哺乳动物雷帕霉素蛋白 

分 类 号：R74[医药卫生—神经病学与精神病学]