骨髓间充质干细胞改善APP/PS1模型小鼠认知功能的机制  

Mechanism by which bone marrow mesenchymal stem cells improve cognitive function in APP/PS1 double transgenic mice

作　　者：谷青芳[1] 郭敏芳[1] 刘晓琴 穆秉桃 李伟梅 宋丽娟 柴智 马存根[1,2] 尉杰忠 Gu Qingfang;Guo Minfang;Liu Xiaoqin;Mu Bingtao;Li Weimei;Song Lijuan;Chai Zhi;Ma Cungen;Yu Jiezhong(Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases,Shanxi Datong University,Datong 037009,Shanxi Province,China;Research Center of Neurobiology,Key Laboratory of Multiple Sclerosis,Nourishing Qi and Activating Blood of State Administration of Traditional Chinese Medicine,Shanxi University of Chinese Medicine,Taiyuan 030629,Shanxi Province,China)

机构地区：[1]山西大同大学神经炎症及变性疾病基础与应用研究山西省重点实验室,山西省大同市037009 [2]山西中医药大学神经生物学研究中心,国家中医药管理局多发性硬化益气活血重点研究室,山西省太原市030629

出　　处：《中国组织工程研究》2022年第19期2964-2969,共6页Chinese Journal of Tissue Engineering Research

基　　金：药用资源与天然药物化学教育部重点实验室开放课题(2019004),项目负责人:马存根;山西省重点实验室神经变性疾病项目(201805D111009),项目负责人:马存根;山西省重点实验室神经变性疾病项目(201805D131005),项目负责人:尉杰忠;山西省大同市科技局基础研究计划(2017136),项目负责人:谷青芳;山西省应用基础研究计划项目(201901D111334),项目负责人:宋丽娟;山西省应用基础研究计划项目(2018TD-012),项目负责人:柴智;中国科学院分子发育生物学国家重点实验室开放课题(2020-MDB-KF-09),项目负责人:宋丽娟。

摘　　要：背景:研究表明,骨髓间充质干细胞治疗可以有效填补阿尔茨海默病患者丢失的神经元,但具体的作用机制有待进一步明确。目的:探讨骨髓间充质干细胞对APP/PS1双转基因阿尔茨海默病模型小鼠的治疗作用及其机制。方法:选取APP/PS1双转基因小鼠作为研究对象,随机分为模型组和骨髓间充质干细胞组,每组10只,选取10只同月龄同性别野生型C57BL/6小鼠作为正常对照组。经鼻腔给予骨髓间充质干细胞(1×10^(6)/次)或生理盐水,每周重复给药1次,持续给药2个月。使用水迷宫检测小鼠的认知功能,Western blot检测小鼠脑组织中病理标志相关因子、炎症信号因子、氧化应激蛋白的表达。结果与结论:骨髓间充质干细胞能有效改善阿尔茨海默病小鼠的认知功能障碍,增加APP蛋白表达,减少磷酸化Tau蛋白表达,降低Toll样受体2、一氧化氮合酶、核转录因子κB的表达,增加核因子E2相关因子2和血红素加氧酶1的表达。结果表明,骨髓间充质干细胞具有治疗阿尔茨海默病的潜在作用,其机制可能通过核因子E2相关因子2/血红素加氧酶1信号通路发挥抗炎、抗氧化作用。BACKGROUND:Studies have shown that bone marrow mesenchymal stem cell therapy can effectively fill the neurons lost in Alzheimer’s disease patients,but the specific mechanism of action needs to be further clarified.OBJECTIVE:To explore the therapeutic effects of bone marrow mesenchymal stem cells in APP/PS1 double transgenic mice with Alzheimer’s disease and its mechanism.METHODS:APP/PS1 double transgenic mice were selected as the research objects and were randomly divided into model and bone marrow mesenchymal stem cell groups(n=10 per group).Ten wild-type C57 BL/6 mice of the same month and the same sex were selected as the normal control group.The mice were treated with bone marrow mesenchymal stem cells(1×10^(6)/time)or normal saline,and repeated administration once a week,for 2 months via nasal cavity.Morris water maze test was applied to examine cognitive function of mice.Western blot assay was used to detect the expression of related factors of pathological markers,inflammatory molecules and oxidative stress proteins in the brain tissues of mice.RESULTS AND CONCLUSION:Bone marrow mesenchymal stem cells effectively improved the cognitive dysfunction of Alzheimer’s disease mice,increased the expression of APP protein and decreased expression of phosphorylated tau protein,reduced the expression of Toll like receptor 2,inducible nitric oxide synthase,nuclear transcription factor kappa B and increased the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1.It is concluded that bone marrow mesenchymal stem cells have a potential role in the treatment of Alzheimer’s disease;the mechanism exerts the effects of the anti-inflammation and antioxidation through nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway.

关 键 词：干细胞 骨髓间充质干细胞 阿尔茨海默病 氧化应激 核因子E2相关因子2 血红素加氧酶1 信号通路 

分 类 号：R459.9[医药卫生—治疗学] R-33[医药卫生—临床医学]