黄芪甲苷通过影响NogoA/NgR和cAMP/PKA通路改善APP/PS1转基因小鼠认知功能  

Astragaloside IV improves cognitive function in APP/PS1 transgenic mice by affecting NogoA/NgR and cAMP/PKA pathways

作　　者：于婧文[1] 郭敏芳[1] 李梦迪 李娜 孟涛 张海飞[1] 宋丽娟 马存根[1,2] 尉杰忠[1,2,4] YU Jingwen;GUO Minfang;LI Mengdi;LI Na;MENG Tao;ZHANG Haifei;SONG Lijuan;MA Cungen;YU Jiezhong(Institute of Brain Science/Department of Neurology of First Affiliated Hospital,Shanxi Datong University,Datong 037009,China;The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Scle-rosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology,Shanxi University of Chinese Medicine,Jinzhong 030619,China;Departemnt of Physiology,Shanxi Medical University,Taiyuan 030001,China;The Fourth People's Hospital of Datong,Datong 037009,China)

机构地区：[1]山西大同大学脑科学研究所/附属第一医院神经科,山西大同037009 [2]山西中医药大学国家中医药管理局多发性硬化益气活血重点研究室/神经生物学研究中心,山西晋中030619 [3]山西医科大学生理学系,山西太原030001 [4]山西大同市第四人民医院,山西大同037009

出　　处：《中国病理生理杂志》2023年第7期1188-1198,共11页Chinese Journal of Pathophysiology

基　　金：山西省基础研究计划(No.20210302123337,No.20210302123478);国家中医药管理局多发性硬化益气活血重点研究室开放课题(No.2021-KF-08T);大同市应用基础研究计划项目(No.2020145,No.2020149);大同大学校科研项目(No.2022K17)。

摘　　要：目的:观察黄芪甲苷(astragaloside Ⅳ, AST Ⅳ)对阿尔茨海默病(Alzheimer disease, AD)模型小鼠认知功能障碍和病理改变的影响,并探讨可能的调控机制。方法:将APP/PS1转基因(APPswe/PSEN1d E9)小鼠随机分为AD+AST Ⅳ组和AD组,并以C57BL/6野生型(wild-type, WT)小鼠作为对照组(WT组),灌胃治疗两个月(n=8)。应用Morris水迷宫和Y迷宫实验评价小鼠空间认知功能(n=8),尼氏染色检测神经元数量与形态,免疫荧光染色观察神经元核抗原(neuronal nuclear antigen, NeuN)和β-淀粉样蛋白(amyloid β-protein, Aβ)水平(n=4),Western blot法检测全脑组织中神经突生长抑制因子A(neurite outgrowth inhibitor A, NogoA)、Nogo-66受体(Nogo-66 receptor, NgR)、p75神经营养因子受体(p75 neurotrophin receptor, p75NTR)、含富亮氨酸重复序列和免疫球蛋白样结构域蛋白1(leucine rich repeat and immunoglobin-like domain-containing protein-1, LINGO-1)、环磷酸腺苷(cyclic adenosine monophosphate, cAMP)和蛋白激酶A(protein kinase A, PKA)的表达(n=4)。结果:AST Ⅳ能够显著缓解APP/PS1小鼠的认知功能障碍,提高其学习、记忆和探索功能。与WT组相比,APP/PS1小鼠大脑皮质区和海马区Aβ沉积增加(P<0.01),尼氏小体丢失严重(P<0.05或P<0.01),神经元数量减少(P<0.05);而AST Ⅳ可以显著减少Aβ沉积(P<0.05),减少尼氏小体丢失(P<0.05),增加神经元数量(P<0.05)。与WT组相比,APP/PS1小鼠脑组织NogoA、NgR、p75NTR和LINGO-1表达显著增加(P<0.05或P<0.01),cAMP和PKA表达显著减少(P<0.05或P<0.01);而AST Ⅳ可以显著抑制NogoA、NgR、p75NTR和LINGO-1表达(P<0.05或P<0.01),增加cAMP和PKA表达(P<0.05)。结论:AST Ⅳ通过抑制NogoA及NgR/p75NTR/LINGO-1受体复合物的表达,并上调cAMP/PKA通路,减少APP/PS1小鼠脑组织中Aβ沉积,减轻神经元损伤,从而改善认知功能和缓解学习障碍。AIM:To investigate the effect of astragaloside Ⅳ(AST Ⅳ)on cognition and pathology in Alzheimer disease(AD)mouse model,and to explore its underlying possible mechanism.METHODS:The APP/PS1 transgenic mice were randomly classified into AD+AST Ⅳ and AD groups,and C57BL/6 wild-type(WT)mice were used as control group(WT group).The mice were treated by intragastric administration for 2 months.Morris water maze and Y-maze tests were performed to evaluate the spatial cognitive function of the mice.Nissl staining was used to detect the number and morphology of neurons,while immunofluorescence staining was used to detect neuronal nuclear antigen(NeuN)and amyloidβ-protein(Aβ)levels.The expression levels of neurite outgrowth inhibitor A(NogoA),Nogo-66 receptor(NgR),p75 neurotrophin receptor(p75NTR),leucine rich repeat and immunoglobin-like domain-containing protein-1(LINGO-1),cyclic adenosine monophosphate(cAMP),and protein kinase A(PKA)in the whole brain were detected by Western blot.RESULTS:Treatment with AST IV significantly improved cognitive function in APP/PS1 mice,and enhanced learning,memory and exploration abilities.Compared with WT mice,APP/PS1 mice exhibited increased Aβdeposition in the cerebral cortex and hippocampus(P<0.01),significant loss of Nissl bodies(P<0.05 or P<0.01),and decreased number of neurons(P<0.05).However,AST IV treatment significantly reduced Aβdeposition(P<0.05)and the loss of Nissl bodies(P<0.05),and increased the number of neurons(P<0.05).Compared with WT mice,the expression levels of NogoA,NgR,p75NTR and LINGO-1 in the whole brain tissue of APP/PS1 mice were significantly increased(P<0.05 or P<0.01),whereas those of cAMP and PKA were significantly decreased(P<0.05 or P<0.01).However,AST IV treatment significantly inhibited the expression of NogoA,NgR,p75NTR and LINGO-1(P<0.05 or P<0.01),and increased the expression of cAMP and PKA(P<0.05).CONCLUSION:Treatment with AST IV reduced Aβdeposition and neuronal damage in the brains of APP/PS1 mice by inhibiting the expression of NogoA an

关 键 词：黄芪甲苷 阿尔茨海默病 NogoA/NgR信号通路 cAMP/PKA信号通路 

分 类 号：R338.2[医药卫生—人体生理学] R741.02[医药卫生—基础医学]