好忘方改善AD模型小鼠认知障碍及机制研究  

Haowang Formula Improved Cognitive Impairment in AD Mice Models and Related Mechanism

作　　者：郭小燕 张海楼[1] 夏宝妹[1] 陶伟伟[1] 李文佳 徐联调 沈琴琴 邹之璐 陈刚[1] GUO Xiao-yan;ZHANG Hai-lou;XIA Bao-mei;TAO Wei-wei;LI Wen-jia;XU Lian-tiao;SHEN Qin-qin;ZOU Zhi-lu;CHEN Gang(Center for Translational Systems Biology and Neuroscience, and Key Laboratory of Integrative Biomedicine for Brain Diseases, Nanjing University of Chinese Medicine, Nanjing, 210023, China)

机构地区：[1]南京中医药大学转化系统生物学与神经科学研究中心,中医脑病研究重点实验室,江苏南京210023

出　　处：《南京中医药大学学报》2020年第6期831-836,共6页Journal of Nanjing University of Traditional Chinese Medicine

基　　金：国家自然科学基金(81673625);江苏省自然科学基金(BK20151568);江苏高校优势学科建设工程资助项目(PAPD)。

摘　　要：目的探讨好忘方(HWF)对阿尔茨海默病(AD)模型小鼠认知障碍改善作用及其与PKA介导的磷酸化TAU的清除和突触可塑性的增强的关系。方法选用东莨菪碱小鼠模型和SAMP8小鼠模型,分别给予1周和3周的药物治疗,分为空白对照组(CTL)、模型对照组(Veh)、好忘方组和多奈哌齐组(Donepezil)。给药结束后通过Morris水迷宫(MWM)和新物体识别(NOR)检测小鼠的认知水平。Western blot检测SAMP8小鼠各组海马中PKA-GSK3β-TAU通路与PKA-CREB及其下游SYNAPSIN1、GLUR1、PSD95、BDNF的蛋白水平变化。结果东莨菪碱模型下给药1周后,Morris水迷宫测试中,好忘方组和多奈哌齐组站台穿越次数与模型对照组相比明显增多(P<0.01)。SAMP8模型下给药3周后,好忘方和多奈哌齐逆转了SAMP8小鼠MWM逃避潜伏期的增加,站台穿越次数及NOR指数的减少(P<0.01),激活PKA-GSK3β-TAU通路降低了TAU-Ser404蛋白水平(P<0.01),并逆转了SAMP8小鼠海马中PKA-CREB及其下游BDNF和突触蛋白SYNAPSIN1、GLUR1、PSD95蛋白水平的下降(P<0.05~0.01)。且好忘方能够逆转SAMP8小鼠MWM目标象限路程比的下降(P<0.05),并在改善MWM逃避潜伏期方面优于多奈哌齐(P<0.05)。结论好忘方可改善AD模型小鼠认知障碍,这与PKA介导的磷酸化TAU的清除和突触可塑性的增强密切相关。OBJECTIVE To assess the effect of Haowang Formula(HWF)in treating Alzheimer's disease(AD)cognitive impairment using scopolamine mice model and senescence accelerated mice P8(SAMP8)model,and investigated the underlying mechanism centered on PKA-mediated clearance of phosphorylated TAU and enhancement of synaptic plasticity.METHODS Mice were randomly divided into 4 groups in both models:Control group(CTL),Model group(Veh),Haowang Formula group and Donepezil group(Donepezil).Morris water maze(MWM)and novel object recognition test(NOR)were used to evaluate the cognitive ability of mice.Western Blot was used to detect the protein levels in PKA-GSK3β-TAU,PKA-CREB and its downstream molecule BDNF and synaptic proteins including SYNAPSIN1,GLUR1,and PSD95 in the hippocampus of SAMP8.RESULTS Under scopolamine model,compared to Model group,HWF and Donepezil distinctly improved times of crossing the platform in Morris water maze.Under SAMP8 model,both HWF and donepezil displayed therapeutic effect on escape latency and times of crossing the platform in MWM,and new object recognition index in NOR(P<0.01).However,HWF increased distance in target quadrant and showed better treatment effect on shortening escape latency than donepezil(P<0.01).In hippocampus of SAMP8 mice,HWF distinctly reduced the protein levels of TAU-ser404 by activating PKA-GSK3β-TAU pathway(P<0.01).It also reversed the down-regulation of PKA-CREB and its downstream molecule BDNF and synaptic proteins including SYNAPSIN1,GLUR1,and PSD95(P<0.05,P<0.01).CONCLUSION HWF can improve cognitive impairment in AD mice models,which is related to PKA-mediated clearance of phosphorylated TAU and enhancement of synaptic plasticity.

关 键 词：阿尔茨海默病 好忘方 SAMP8 东莨菪碱 认知障碍 磷酸化TAU 突触可塑性 

分 类 号：R285.5[医药卫生—中药学]