中文摘要：

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.

英文摘要：

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.