不同时程APP转基因小鼠学习记忆改变及参乌胶囊、二苯乙烯苷的干预作用

Learning memory deficit in APP transgenic model of Alzheimer’s disease and intervention by Shen-wu capsule and its effective component

目的观察不同时程拟阿尔茨海默病(Alzheimer’sdisease,AD)转基因动物模型学习记忆能力改变,以及中药参乌胶囊及其有效成分二苯乙烯苷(TSG)防治AD的药理机制。方法拟AD动物模型为4到16月龄APP695V717I转基因小鼠。4月龄起灌胃给予参乌胶囊及TSG6个月。另一批未处理的APP转基因小鼠饲养至10月龄开始灌胃给予TSG6个月。同背景同月龄C57BL/6J小鼠为正常对照组。行为学检测应用Morris水迷宫实验和物体识别实验。结果早期4月龄APP转基因小鼠即出现学习记忆能力障碍,水迷宫游出时间比对照组延长46.1%,物体识别检测的分辨指数相差2.96倍。增龄至10月龄,正常对照组小鼠学习记忆能力无明显变化,而APP转基因小鼠学习记忆能力急剧下降,水迷宫游出时间与对照组的差异加大为95%,物体识别中分辨指数更相差6.7倍。增龄至晚期16月龄,对照组的老化使其学习记忆能力与10月龄相比也明显下降。虽然APP模型组仍表现明显的学习记忆能力障碍,但差距缩小,水迷宫游出时间与对照组的差异为49.1%,在物体识别中分辨指数只相差2.95倍。参乌胶囊和TSG可明显改善10月龄APP转基因小鼠Morris水迷宫作业成绩,提高模型鼠物体识别能力。对10月龄已出现病理变化的模型鼠灌服TSG6个月后,也可明显改善16月龄APP转基因小鼠Morris水迷宫作业成绩,提高模型鼠物体识别能力。结论4月龄、10月龄、16月龄APP695V717I转基因小鼠模型较好地模拟早期、中期、晚期AD患者的学习记忆缺陷,可用于AD发病机理和防治AD药物作用机制的研究。参乌胶囊及其有效成分二苯乙烯苷不仅能早期预防学习记忆障碍的发生,还能逆转和治疗已出现的学习记忆障碍,对防治AD等神经退行性疾病具有良好的应用前景。

Objective To investigate learning-memory deficit in the different age of AD-like animal model and the protective effect of Shen-wu capsule and its effective component-2,3,5,4-tetrahydroxy stilbene-2- O-β-D- glucoside（TSG） on learning-memory ability. Methods AD-like APP V717[ transgenic（Tg） mouse was observed from 4 to 16 months old. The Tg mice were randomly divided into 3 model groups（4 months 10 months and 16 months old） , Shen-wu capsule group and TSG group, The animals were administered intragastrically by the drugs from 4 to 10 months old. For un-treated 10 months APP Tg mice, TSG were administrated to them from 10 to 16 months old. Control adapted the same age and background C57BL/6J mice. Learning-memory ability was detected by Morris water maze（MWM） and object recognition test（ORT）. Results For 4 month old APP Tg mice, learning-memory deficit appeared. The swimming time and distance increased in MWM and the discrimination index decreased in ORT. For 10 months old APP Tg mice, learning-memory deficit aggravated. Both Shen-wu capsule and TSG could decrease the swimming time in MWM and increase the discrimination index in ORT, For 16 month old APP Tg mice, learning-memory deficit still exist but abated a lot. TSG could improve learning-memory ability both in MWM and ORT. Conclusion APP Tg mice from young to old mimic the learning-memory deficit in early, middle and late stage of AD. APP transgenic mice in 10 month old shows most significant learning-memory deficit and is most suitable to he used in the study for the pathology of Alzheimer＇ s disease and pharmacological mechanism of drugs on AD therapy. Shen-wu capsule and Tetrahydroxystilbene glucoside not only prevent the learningmemory deficit in early stage of AD-like model but also reverse the learning-memory deficit in late stage of AD-like model, so they would be applied in tile treatment for AD and other neurodegenerative diseases.