APP/PS-1/Tau雌性小鼠模拟女性AD病理模型的评价研究

Evaluation of APP/PS-1/Tau Female Mice to Simulate the Pathological Model of Female AD

目的:筛选一种与女性阿尔茨海默病(Alzheimer’s disease,AD)病证相应的动物模型,为研究AD的复合治疗靶点提供基础。方法:以3×Tg-AD雌性小鼠为研究对象,雌性野生型C57BL/6J(wild type,WT)小鼠为对照,Elisa检测体内雌激素水平,HE染色观察股骨骨量差异和卵巢衰老情况,Morris水迷宫检测小鼠空间学习记忆;免疫荧光染色检测海马区APP/PS-1/Tau蛋白表达情况,Nissl染色观察脑内神经元尼氏小体情况。结果:3、6、10月龄雌性小鼠体内雌激素、股骨骨量和卵巢具有明显时间依赖的下调趋势;Morris水迷宫结果显示,3×TgAD小鼠在6、10月龄水迷宫实验中的逃避潜伏期高于WT小鼠;海马区免疫荧光染色提示3×Tg-AD小鼠在10月龄时Aβ/PS-1/Tau表达明显增多。与对照组相比,3月龄3×Tg-AD小鼠海马区神经元排列整齐,细胞层次清晰、胞体较大,且无明显差别,6月龄3×Tg-AD小鼠神经元排列疏松,尼氏体溶解消失、数目减少现象,10月龄神经元排列、神经元凋亡等现象更为明显。结论:10月龄3×Tg-AD小鼠出现学习记忆障碍明显,脑内Aβ聚积和Tau增多,体内测定雌激素水平下降显著,股骨骨量差异明显且卵巢凋亡迹象显著等特点,契合绝经后女性AD临床病理表现和症状,为理想的女性痴呆模型。

Objective:To screen an animal model that is compatible with female AD syndrome and to provide a basis for the study of compound therapeutic targets for AD.Methods:3×Tg-AD female mice as the research object and C57BL/6J(wild type,WT)female mice as the control,the estrogen level in vivo was detected by Elisa.Differences in femoral bone mass and ovarian aging were observed by HE staining.The spatial learning and memory of mice were measured by Morris water maze.Immunofluorescence staining was used to detect the expression of APP/PS-1/Tau protein in the hippocampus.Nissl staining was used to observe the neuronal Nissl bodies in the brain.Results:The estrogen,bone mass of femur and ovary of female mice at the age of 3,6 and 10 months were significantly down-regulated in an age-dependent manner.Morris water maze data showed that the escape latency of 3×Tg-AD mice at the age of 6 and 10months was significantly higher than WT mice.Immunofluorescence staining showed that the co-expression of Aβ/PS-1/Tau protein increased in the hippocampus of 3×Tg-AD mice at 10months of age.Compared with the control group,the neurons in the hippocampus of 3×Tg-AD mice aged 3-month-old were neatly arranged,with clear cell layers and larger cell bodies,with no significant difference.While neurons in 6-month-old 3×Tg-AD mice were loosely arranged,Nissl body dissolved and disappeared,with the number decreased,and the arrangement and apoptosis of neurons in 10-month-old mice were more obvious.Conclusion:The 10-month-old 3×Tg-AD mice had learning and memory impairment,increased Aβaccumulation and Tau in the brain,significantly decreased estrogen levels in vivo,significant differences in femoral bone mass and significant signs of ovarian apoptosis.it coincides with the clinicopathological symptoms of postmenopausal women with AD,which is an ideal female dementia model.