氟西汀通过增加阿尔茨海默病APP/PS1转基因小鼠脑内乙酰胆碱的含量改善其空间学习能力  

Fluoxetine improves the spatial learning ability of APP/PS1 transgenic mice with Alzheimer's disease by increasing the cerebral acetylcholine content

作　　者：黄维[1] 马晶[1] 晁凤蕾 张蕾[1] 唐炜[1] 李常琼 李桃[1] 赵振华[1] 张毅[1] 周春妮[1] 蒋林[1] 唐勇[1] 

机构地区：[1]重庆医科大学基础医学院组织学与胚胎学教研室,干细胞与组织工程学研究室,重庆400016

出　　处：《中国组织化学与细胞化学杂志》2017年第1期29-35,共7页Chinese Journal of Histochemistry and Cytochemistry

基　　金：国家自然科学基金面上项目(81671259,81470057,81501101);重庆市首批“百名学术学科领军人才”培养计划(2012);2016年重庆医科大学优秀博士论文资助项目;2016年重庆市研究生科研创新项目

摘　　要：目的探讨胆碱能神经系统是否是抗抑郁药氟西汀(Fluoxetine,FLXT)改善阿尔茨海默病(Alzheimer's disease,AD)患者大脑空间学习记忆能力的作用靶点。方法随机选取18月龄的雄性APP/PS1双转基因AD小鼠20只分为阳性对照组(APP/PSI组)和FLXT组,分别给予为期4周的腹腔注射生理盐水和FLXT,并随机选取18月龄同窝生野生型(wild type,WT)小鼠10只作为阴性对照组(WT组),该组不给于药物干预。运用Morris水迷宫实验对三组小鼠的空间学习记忆能力进行检测,采用免疫组织化学染色和紫外分光光度法对三组小鼠大脑内β-淀粉样蛋白(amyloidβ-protein,Aβ)沉积情况和乙醜胆碱(acetylcholine,Ach)的含量、乙酰胆碱脂酶(acetylcholinesterase,AchE)及胆碱乙酰化酶(choline acetyl transferase,ChAT)活性等进行检测。结果水迷宫实验显示,APP/PS1小鼠逃避潜伏期显著长于WT小鼠,FLXT处理可明显缩短APP/PS1小鼠逃避潜伏期;免疫组织化学染色显示,WT小鼠脑内未见明显Aβ沉积,而APP/PSI小鼠海马内可见大量Aβ沉积,FLXT处理可明显减少APP/PS1小鼠海马内Aβ沉积;对Ach含量、AchE和ChAT活性检测显示,APP/PS1小鼠大脑皮质及海马内的Ach含量、AchE活性及皮质内的CHAT活性均较WT小鼠降低,FLXT处理可明显抑制APP/PS1小鼠大脑皮质及海马内Ach含量、AchE活性的降低,但对ChAT活性没明显的作用。结论胆碱能系统可能是FLXT作用于AD大脑的作用靶点之一,即FLXT可能通过增加AD大脑胆碱能神经系统的神经功能活性,进而增加Ach的含量,从而改善AD大脑的空间学习记忆能力。Objective To investigate whether the cholinergic system is the target of the antidepressant fluoxetiue （FLXT） which improves the spatial [earning ability and memory of patients with Alzheimer＇s disease （AD）. Methods Twenty 18-month-old male trans- genic APP/PS1 mice with AD were randomly divided into two groups： the positive control group （ APP/PS1 group, n = 10） and the FLXT group （ n = 10）, intraperitoneally injected with normal saline and fluoxetine for four weeks respectively. Another 10 male wild type （WT） mice were randomly selected from the same brood as the negative control group （WT group, n = 10）, on which no medical intervention was exerted. The spatial learning ability and memory of the mice were evaluated by Morris water maze test. Amyloid [3-pro- tein （A-） deposition, acetylcholine （Ach） content, and the activity of acetylcholinesterase （AchE） and choline acetyl transferase （CHAT） were measured by immunohistochemieal staining and ultraviolet spectroscopy. Results In Morris water maze test, the escape latency of APP/PS1 mice was significantly longer than that of WT mice, and was greatly shortened with fluoxetine treatment. Immuno- histochemieal staining showed obvious amyloid plaques deposited in the brain tissue of APP/PS1 mice, and the plaques be reduced with fluoxetine treatment, which were not observed in WT mice. Moreover, the content of A ch and the activity of AchE and ChAT were bothlower in the cerebral cortex and hippocampus of APP/PS1 mice than in WT mice; fluoxetine significantly restrict the decrease of Ach content and AchE activity, but had no effect on the activity of CHAT. Conclusion The cholinergic system might be one of the target of fluoxetine treatment in AD patients. By promoting the functional activity of the cholinergic system, fluoxetine may increase the content of Ach and improve the spatial learning ability and memory of AD brains.

关 键 词：阿尔茨海默病 氟西汀 APP/PS1 β-淀粉样蛋白沉积 乙酰胆碱 胆碱乙酰化酶 乙酰胆碱酯酶 

分 类 号：R965.2[医药卫生—药理学]