产前应激加剧慢性子代应激诱导的子鼠学习记忆能力损伤

目的探讨产前应激是否进一步加剧慢性应激所致的6月龄雄性APPswe/PS1dE9子鼠学习记忆损伤及其可能机制。方法以 APPswe/PS1dE9双转基因小鼠为研究对象，实验分为产前慢性应激-子代慢性应激组( TT组)、产前慢性应激-子代正常处理组( TC组)、产前正常处理-子代慢性应激组( CT组)和产前正常处理-子代正常处理组( CC组)。应用Morris水迷宫检测子代小鼠的空间学习、记忆能力，通过HE染色观察小鼠海马CA3区神经元的病理组织形态，采用Congo red染色检查小鼠脑组织的淀粉样斑块，采用 Western blot 法检测小鼠海马组织淀粉样前体蛋白(APP)、淀粉样前体蛋白β位点分裂酶1(BACE1)和β-淀粉样蛋白1-42( Aβ42)的表达量，运用ELISA法检测血清皮质酮含量。结果与CC组相比， CT组小鼠的逃避潜伏期
　　和游泳距离延长(P<0．05)，平台象限游泳时间和穿越平台次数减少(P<0．05)；海马CA3区损伤的神经元数目明显增加(P<0．05)，排列疏松紊乱，脱失现象明显，核固缩、浓染；脑组织淀粉样斑块数目增多；海马组织APP、BACE1和Aβ42的表达量升高( P <0．05)；血清皮质酮浓度升高(P<0．05)。与CT组相比， TT组小鼠的逃避潜伏期和游泳距离进一步延长(P<0．05)，平台象限游泳时间和穿越平台次数进一步减少( P <0．05)；脑组织淀粉样斑块和海马CA3区损伤的神经元数目进一步增加(P<0．05)；海马组织APP、BACE1和Aβ42的表达量和血清皮质酮浓度进一步升高(P<0．05)。结论产前应激进一步加剧慢性应激所致的子鼠学习记忆损伤，其机制可能与其升高小鼠血清皮质酮水平，促进APP和BACE1表达，进而增加Aβ42的生成，最终引起海马CA3区神经元损伤有关。

Chronic prenatal stress exacerbates learning and memory impairments in adult male APPswe/PS1 dE9 offspring mice who also suffer chronic stress

Objective To determine whether chronic prenatal stress could exacerbate learning and memory impair-ments in 6-month-old male APPswe/PS1dE9 offspring mice who also suffer chronic stress, and if so, what the un-derlying mechanism is. Methods There were four groups: the prenatal control-offspring control group ( CC group), the prenatal control-chronic offspring stress group (CT group), the chronic prenatal stress-offspring control group ( TC group) , and the chronic prenatal stress-chronic offspring stress group ( TT group) . Morris water maze was used to investigate learning and memory impairments in mice, and the histopathologic changes in CA3 field of the hippocampus ( HE stain and Congo red stain) in hippocampus were examined under a light microscope. Fur-thermore, western blot was used to observe the expression levels of amyloid precursor protein ( APP) ,β-site APP-cleaving enzyme 1 (BACE1) and amyloid-βprotein (Aβ42) in hippocampus. Additionally, we also used ELISA to examine the serum levels of corticosterone in the offspring mice. Results Compared with the CC group, the results showed that CT group mice had more escape latency and swimming distance ( P<0. 05 ) , less number of crossing the platform site and swimming time in the quadrant of the platform (P<0. 05). Furthermore, the neuropathologi-cal changes were characterized by the disintegrated pyramidal layered structure, decreased neuron number, worse cell morphology, soma condensation, nuclear pyknosis in the CA3 field of hippocampus in the CT group ( P <0. 05). Moreover, the expression of APP, BACE1 and Aβ42 in hippocampus were increased, as well as the serum corticosterone concentration in the CT group (P<0. 05). Noteworthy, the learning and memory impairments and neuropathological changes stated above were worse in TT group mice compared to CT group mice ( P <0. 05 ) . Conclusion Chronic stress could exacerbate learning and memory impairments in 6-month-old male APPswe/PS1dE9 offspring mice who also suffer chronic stress, which may be related to chronic prenatal stress potentiate the production of Aβ42 mediated by glucocorticoids through increasing expression of APP and BACE1 gene.