氟西汀对APP/PS1双转基因阿尔茨海默病模型小鼠记忆能力的改善作用及其机制

Study on the Mechanism and Improvement of APP/PS1 Double Transgenic AD Mice's Learning and Memory by Fluoxetine

本研究初步探讨氟西汀(Fluoxetine)改善淀粉样蛋白前体蛋白(β-amyloid precursor protein,APP)/早老素1(presenilin 1,PS1)双转基因阿尔茨海默病(Alzheimer's disease,AD)模型小鼠的学习记忆能力及可能机制。采用APP/PS1双转基因AD模型雄性小鼠,随机分成氟西汀处理组(FLU)和生理盐水组(NS),分别给予氟西汀10 mg·kg-1·d-1和等量生理盐水腹腔注射60 d。药物处理后行水迷宫检测小鼠学习记忆能力,采用尼氏染色观察海马神经元数量的变化,用免疫组化检测海马的Ach E的变化。水迷宫定位航行实验结果显示氟西汀组较生理盐水组的逃避潜伏期、总路程明显缩短(p<0.05),游泳速度无明显差异;空间探索实验氟西汀组穿台次数较生理盐水组明显增加(p<0.05)。尼氏染色结果显示氟西汀组在CA1区神经元数量和生理盐水组无显著性差异(p>0.05),氟西汀组在DG区神经元数量比生理盐水组明显增多(p<0.05)。乙酰胆碱酯酶(Ach E)免疫组化染色结果显示氟西汀组在海马CA1、DG区乙酰胆碱酯酶表达量较生理盐水组明显减少(p<0.05)。穿台次数与CA1和DG区Ach E的表达量之间的有显著性的相关性(CA1区r=-0.791,p=0.002,DG区r=-0.839,p=0.001)。本研究结果提示氟西汀可通过减少AD小鼠海马DG区神经元的数量丢失和下调AD小鼠海马区Ach E表达量而改善AD模型小鼠的空间学习记忆能力。

To discuss whether Fluoxetine improve the ability of learning and space learning memory of APP/PS12×Tg Alzheimer's Disease Mice. Further to discuss whether the protective effect of Fluoxetine through decreased the expression of Ach E and reduced the loss of neurons in hippocampus. Experimental animals were divided into two groups: APP/PS1 AD model injection of Fluoxetine(FLU) group(n=6), APP/PS1 AD model saline group(NS)(n=6). After intraperitoneal injection of fluoxetine 10 mg·kg-1·d-1for 60 days, Morris water maze test was used to assess the cognitive behavioristics in each group. Nissl staining was applied to quantify neurons in hippocampus.Immunohistochemistrical staining was use to analyze the expression of Ach E in hippocampus. In Morris water maze place navigation trial, the FLU group reduce the time of latency and cumulative distance significantly compared with the NS group(p<0.05, n=6). There was no significant difference on swimming speed between the two group. In spatial probe trial, the FLU significantly improved the number of crossing the plate. Immunohistochemistry staining of the Ach E shows that positive intensity in FLU group are less than NS group(p<0.05, n=6). Nissl staining shows that hippocampus neurons in FLU group were significantly more than that of NS group(p<0.05, n=6). The number of crossing the plate was negatively related to the IOD of Immunohistochemistry staining of the Ach E in area CA1(r=-791, p=0.002) and DG(r=-70.839, p=0.001) of hippocampus. Long-term administration of fluoxetine significantly decreased AD model mice Ach E expression in hippocampus, reduced the loss of neurons in hippocampus and improved the ability of learning and memory in APP/PS1 2×Tg Alzheimer's Disease Mice.