Objective: To exploer the effect of mammalian target ofrapamycin(mTOR)on cognitive dysfunction of mice with Alzheimer's disease (AD) induced by amyloid β(1-42) (Aβ(1-42)) 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 Aβ(1-42)); DMSO group(AD mice induced by Aβ(1-42) were intraperitoneally injected with dimethylsulfoxide for 14 days);RAPA group(AD mice induced by Aβ(1-42) 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 Aβ(1-42), 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 Aβ(1-42) 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 Aβ(1-42) 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 Aβ(1-42) and reduce deposition of Aβ(1-42) 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.
目的： 通过观察哺乳动物雷帕霉素靶蛋白（mTOR）对淀粉样蛋白β(1-42)（Aβ(1-42)）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Aβ(1-42)）、二甲基亚砜（DMSO）组（海马注射Aβ(1-42)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Aβ(1-42)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Aβ(1-42)、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Aβ(1-42)、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Aβ(1-42)、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Aβ(1-42)所致AD小鼠行为认知功能障碍，减少脑内Aβ(1-42)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。.
Keywords: Alzheimer′s disease; Amyloid β(1-42); Mammalian target ofrapamycin; Phosphorylate-mammalian target of rapamycin; Rapamycin.