T-006改善APP/PS 1/Tau转基因小鼠学习记忆功能及调控突触相关蛋白表达  

T-006 Improves Learning and Memory Function and Regulates Synaptic Associated Protein Expression in APP/PS 1/Tau Triple Transgenic Mice

作　　者：程洁鸿 张桂梁 郭宝剑[2] 孙业伟[2] 张高小[2] 王玉强[2] 张在军[2] CHENG Jie-hong;ZHANG Gui-liang;GUO Bao-jian;SUN Ye-wei;ZHANG Gao-xiao;WANG Yu-qiang;ZHANG Zai-jun(The First Affiliated Hospital,Guangzhou University of Chinese Medicine,Guangzhou 510405,China;Institute of New Drug Research,College of Pharmacy,Jinan University,Guangzhou 510632,China)

机构地区：[1]广州中医药大学第一附属医院,广东广州510405 [2]暨南大学药学院新药研究所,广东广州510632

出　　处：《中山大学学报（医学科学版）》2021年第5期667-675,共9页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：国家自然科学基金NSFC-FDCT联合项目(82061160374);国家科技部“十三五”新药创制重大专项项目(2019ZX09301172);广东省自然科学基金(2019A1515110751,2020A1515011061)。

摘　　要：【目的】在阿尔茨海默病(AD)APP/PS1/Tau(3×Tg)转基因小鼠模型中,探究四甲基吡嗪衍生物T-006改善3×Tg转基因小鼠学习与记忆功能的效果和机理。【方法】本研究以8月龄的3×Tg小鼠及同窝野生型小鼠为研究对象,实验小鼠分为WT组、WT+T-006(10 mg/kg)组、3×Tg组、T-006低中高剂量组(1、3和10 mg/kg)、多奈哌齐组(1.3 mg/kg)、美金刚组(5 mg/kg);T-006、多奈哌齐1 d给药1次,美金刚1 d给药2次,连续给药4个月;利用新物体识别、电跳台和水迷宫等行为学,对小鼠的学习与记忆能力进行评估;采用免疫组化技术观察小鼠海马区淀粉样蛋白斑块沉积;Westernblotting检测APP、BACE-1、PSD95、synapsinⅠ、synpainⅡ、synaptophysin、BDNF、CREB和p-CREB蛋白的表达。【结果】与模型相比,T-006显著性地减少小鼠在电跳台实验中的犯错次数(P<0.05)。West⁃ernblotting结果显示,T-006可以显著性降低APP蛋白表达,增加PSD95、synaptophysin、synapsinⅠ、BDNF蛋白表达(P<0.05)。【结论】T-006改善3×Tg小鼠的学习与记忆能力,降低APP蛋白表达,可能与增加突触相关蛋白的表达有关。【Objective】To investigate the efficacy and mechanism of tetramethylpyrazine derivative T-006 on learning and memory function of APP/PS1/Tau transgenic(3×Tg)mice.【Methods】Eight-month-old 3×Tg mice and their wild-type(WT)littermates were divided into WT group,WT+T-006(10 mg/kg)group,3×Tg group,low-dose T-006 group(1 mg/kg),medium-dose T-006 group(3 mg/kg),high-dose T-006 group(10 mg/kg),donepezil group(1.3 mg/kg)and memantine group(5 mg/kg). Within 4 months,T-006 and donepezil were continuously administered once a day and memantine twice a day. Behavioral tests including novel object recognition,step-down avoidance and morris water maze were performed to evaluate learning and memory function of mice. Immunohistochemistry was used to observe the deposition of amyloid plaques in the hippocampus of mice. Western blotting was employed to detect the protein expression of APP,BACE-1,PSD95,synapsin Ⅰ,synapsin Ⅱ,synaptophysin,BDNF,CREB and p-CREB.【Results】T-006 treatment reduced the numbers of errors in the step-down avoidance test(P< 0.05),significantly reduced the APP expression and increased the expression of PSD95,synaptophysin,synapsin Ⅰ and BDNF(P<0.05).【Conclusion】T-006 improves the learning and memory function of 3×Tg mice and reduces the APP expression,which may be explained by the increase of synaptic associated protein expression.

关 键 词：四甲基吡嗪衍生物T-006 APP/PS1/Tau 阿尔茨海默病 突触蛋白 学习与记忆 

分 类 号：R964[医药卫生—药理学]