中华神经科杂志
中華神經科雜誌
중화신경과잡지
Chinese Journal of Neurology
2012年
2期
102-106
,共5页
陆剑平%曾育琦%沈辉%张静%朱元贵%陈晓春
陸劍平%曾育琦%瀋輝%張靜%硃元貴%陳曉春
륙검평%증육기%침휘%장정%주원귀%진효춘
阿尔茨海默病%羟肟酸类%小鼠,转基因%tau蛋白质类%糖原合成酶激酶类
阿爾茨海默病%羥肟痠類%小鼠,轉基因%tau蛋白質類%糖原閤成酶激酶類
아이자해묵병%간우산류%소서,전기인%tau단백질류%당원합성매격매류
Alzheimer disease%Hydroxamic acids%Mice,transgenic%tau Proteins%Glycogen synthase kinases
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.
目的 觀察組蛋白去乙酰化酶抑製劑(HDACi)對阿爾茨海默病轉基因小鼠認知功能和腦內tau蛋白燐痠化的影響.方法 分彆選擇12隻5XFAD轉基因(5XFAD-CC)和野生型(WT)小鼠,採用HDACi伏立諾他(SAHA,每組7隻)與溶媒對照(每組5隻)處理動物,利用Y-迷宮、Morris水迷宮評估5XFAD-CC小鼠學習和記憶能力,通過蛋白免疫印跡檢測α-tubulin乙酰化、tau和糖原閤成激酶3β(GSK313)蛋白及其燐痠化水平.結果 SAHA可改善5XFAD-CC小鼠即刻記憶、工作記憶能力,SAHA組進入新奇區域的次數(39.10％ ±2.25％,t=2.688,P=0.031)和停留時間(26.81％ ±0.78％,t=3.271,P=0.017)較溶媒對照組(分彆為30.33％±2.32％和19.80％±1.99％)明顯增加；同時,SAHA可改善5XFAD-CC小鼠空間參攷記憶能力,SAHA組尋找平檯的潛伏期較溶媒對照組縮短(F=5.936,P=0.045)及進入原平檯所在象限時間增加(31.70％ ±4.21％,t=2.317,P=0.049).SAHA可增加5XFAD-CC和WT小鼠腦內HDAC6底物α-tubulin乙酰化水平(分彆增加26.42％和29.64％),降低5XFAD-CC小鼠海馬tau-pSer396、tau-pSer404和tau-pThr231燐痠化水平(與溶媒對照組比較,分彆減少24.22％、48.98％和26.95％)及GSK3β燐痠化水平(31.29％).結論 SAHA可改善5XFAD小鼠的學習和記憶能力,可能與其降低tau和GSKSB蛋白燐痠化水平有關.
목적 관찰조단백거을선화매억제제(HDACi)대아이자해묵병전기인소서인지공능화뇌내tau단백린산화적영향.방법 분별선택12지5XFAD전기인(5XFAD-CC)화야생형(WT)소서,채용HDACi복립낙타(SAHA,매조7지)여용매대조(매조5지)처리동물,이용Y-미궁、Morris수미궁평고5XFAD-CC소서학습화기억능력,통과단백면역인적검측α-tubulin을선화、tau화당원합성격매3β(GSK313)단백급기린산화수평.결과 SAHA가개선5XFAD-CC소서즉각기억、공작기억능력,SAHA조진입신기구역적차수(39.10％ ±2.25％,t=2.688,P=0.031)화정류시간(26.81％ ±0.78％,t=3.271,P=0.017)교용매대조조(분별위30.33％±2.32％화19.80％±1.99％)명현증가；동시,SAHA가개선5XFAD-CC소서공간삼고기억능력,SAHA조심조평태적잠복기교용매대조조축단(F=5.936,P=0.045)급진입원평태소재상한시간증가(31.70％ ±4.21％,t=2.317,P=0.049).SAHA가증가5XFAD-CC화WT소서뇌내HDAC6저물α-tubulin을선화수평(분별증가26.42％화29.64％),강저5XFAD-CC소서해마tau-pSer396、tau-pSer404화tau-pThr231린산화수평(여용매대조조비교,분별감소24.22％、48.98％화26.95％)급GSK3β린산화수평(31.29％).결론 SAHA가개선5XFAD소서적학습화기억능력,가능여기강저tau화GSKSB단백린산화수평유관.
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.
