摘要
目的 观察组蛋白去乙酰化酶抑制剂（HDACi）对阿尔茨海默病转基因小鼠认知功能和脑内tau蛋白磷酸化的影响.方法 分别选择12只5XFAD转基因（5XFAD-CC）和野生型（WT）小鼠,采用HDACi伏立诺他（SAHA,每组7只）与溶媒对照（每组5只）处理动物,利用Y-迷宫、Morris水迷宫评估5XFAD-CC小鼠学习和记忆能力,通过蛋白免疫印迹检测α-tubulin乙酰化、tau和糖原合成激酶3β（GSK313）蛋白及其磷酸化水平.结果 SAHA可改善5XFAD-CC小鼠即刻记忆、工作记忆能力,SAHA组进入新奇区域的次数（39.10％ ±2.25％,t=2.688,P=0.031）和停留时间（26.81％ ±0.78％,t=3.271,P=0.017）较溶媒对照组（分别为30.33％±2.32％和19.80％±1.99％）明显增加；同时,SAHA可改善5XFAD-CC小鼠空间参考记忆能力,SAHA组寻找平台的潜伏期较溶媒对照组缩短（F=5.936,P=0.045）及进入原平台所在象限时间增加（31.70％ ±4.21％,t=2.317,P=0.049）.SAHA可增加5XFAD-CC和WT小鼠脑内HDAC6底物α-tubulin乙酰化水平（分别增加26.42％和29.64％）,降低5XFAD-CC小鼠海马tau-pSer396、tau-pSer404和tau-pThr231磷酸化水平（与溶媒对照组比较,分别减少24.22％、48.98％和26.95％）及GSK3β磷酸化水平（31.29％）.结论 SAHA可改善5XFAD小鼠的学习和记忆能力,可能与其降低tau和GSKSB蛋白磷酸化水平有关.
Objective To observe the effects of histone deacetylases inhibitor （HDACi） on cognitive performance and cerebral tau phosphorylation in transgenic mice coexpressed five familial Alzheimer＇ s disease mutations （5XFAD）.Method The total 12 5XFAD-CC and 12 wild type （WT） mice were administrated with suberoylanilide hydroxamic acid （ SAHA,n =7） and vehicle （ n =5 ）,respectively.The cognitive performance was assessed by Y-maze and Morris water maze.The protein levels of acetylated α-tubulin,total tau and phosphorylated tau and phosphorylated glycogen synthase kinase-3β （GSK3β） were determined by Western blotting.Results SAHA ameliorated learning and memory deficits in 5XFAD-CC mice （39.10% ±2.25%,t =2.688,P =0.0312 for total numbers of entrance in novel arm; 26.81% ±0.78%,t =3.271,P =0.017 for time spending in novel arm; F =5.936,P =0.045 for hidden platform;31.70% ±4.21%,t =2.317,P =0.049 for probe trial）.Administration of SAHA significantly increased acetylated α-tubulin in hippocampus of WT and 5XFAD-CC mice （26.42% and 29.64%,respectively）.Additionally,SAHA attenuated tau-pSer396,tau-pSer404 and tau-pThrThr231 in hippocampus of 5XFAD-CC mice （24.22%,48.98% and 26.95%,respectively）. Moreover,hippocampal phosphorylated GSK3β was markedly reduced in SAHA-treated 5XFAD-CC mice （31.29%）. Conclusion SAHA may improve cognitive performance in 5XFAD-CC mice, which is associated with its significant effects on the phosphorylation of tau and GSK3β.
出处
《中华神经科杂志》
CAS
CSCD
北大核心
2012年第2期102-106,共5页
Chinese Journal of Neurology
基金
国家自然科学基金资助项目（81071007）
福建省自然科学杰出青年基金资助项目（2009J06015）
国家人力资源和社会保障部留学人员择优项目和教育部留学回国人员科研启动基金项目
