敲低ROCK2基因通过促进线粒体融合并抑制其分裂改善AD小鼠认知功能及减轻神经细胞凋亡  

Knock-down of ROCK2 gene improves cognitive function and reduces neuronal apoptosis in AD mice by promoting mitochondrial fusion and inhibiting its division

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作  者:郭敏芳[1] 张慧宇 章培军[1] 于婧文[1] 孟涛 李苏垚 宋丽娟 柴智[2] 尉杰忠 马存根[1,2,3] GUO Minfang;ZHANG Huiyu;ZHANG Peijun;YU Jingwen;Meng Tao;LI Suyao;SONG Lijuan;CHAI Zhi;YU Jiezhong;MA Cungen(Institute of Brain Science,Shanxi Datong University,Datong 037009;The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine,Research Center of Neurobiology,Shanxi University of Chinese Medicine,Jinzhong 030619;Department of Physiology,Shanxi Medical University,Taiyuan 030001;The Fourth People's Hospital of Datong,Datong 037008,China)

机构地区:[1]山西大同大学脑科学研究所,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/第一临床医学院,山西太原030001 [4]大同市第四人民医院,山西大同037008

出  处:《细胞与分子免疫学杂志》2023年第8期701-707,共7页Chinese Journal of Cellular and Molecular Immunology

基  金:山西省高等学校科技创新项目(2020L0484);山西省基础研究计划(20210302123476,20210302123478);山西省卫健委医学科技领军团队(2020TD05);基于炎性反应的重大疾病创新药物山西省重点实验室开放课题(202105D121011);山西中医药大学青年科学家培育项目(2021-PY-QN-09)。

摘  要:目的 探讨敲低Rho相关螺旋卷曲激酶2(ROCK2)基因对淀粉样前体蛋白/早老素1(APP/PS1)双转基因小鼠认知功能的影响及其机制。方法 APP/PS1双转基因小鼠随机分为AD模型组(AD组)、 ROCK2基因敲低组(shROCK2组)、 ROCK2基因敲低对照组(shNC组),同龄野生型C57BL/6小鼠作为野生型对照(WT组)。Morris水迷宫和Y迷宫实验测试小鼠认知功能,尼氏染色检测神经元形态,免疫荧光组织化学染色检测磷酸化动力蛋白相关蛋白1(p-Drp1)和线粒体融合蛋白1(Mfn1)的表达,Western blot法检测海马组织ROCK2、裂解型胱天蛋白酶3(c-caspase-3)、 B细胞淋巴瘤因子2(Bcl2)、 Bcl2相关蛋白X(BAX)、 p-Drp1、线粒体分裂蛋白1(Fis1)、视神经萎缩因子1(OPA1)、 Mfn1和Mfn2的蛋白表达。结果 与AD组小鼠相比,shROCK2组小鼠ROCK2表达明显减少;其认知功能明显改善,海马CA3和DG区神经元数量增加,尼氏体染色深;c-caspase-3和BAX表达降低,同时Bcl2表达升高;线粒体分裂相关蛋白p-Drp1和Fis1的表达减少,而线粒体融合相关蛋白OPA1、 Mfn1和Mfn2的表达增加。结论 敲低ROCK2可以显著改善APP/PS1小鼠的认知功能,并抑制神经细胞凋亡,其机制可能与促进线粒体融合并抑制其分裂有关。Objective To explore the effect of knocking down Rho-associated coiled-coil kinase(ROCK2)gene on the cognitive function of amyloid precursor protein/presenilin-1(APP/PS1)double transgenic mice and its mechanism.Methods APP/PS1 double transgenic mice were randomly divided into AD model group(AD group),ROCK2 gene knock-down group(shROCK2 group),ROCK2 gene knock-down control group(shNCgroup),and wild-type C57BL/6 mice of the same age served as the wild-type control(WT group).Morris water maze and Y maze were employed to test the cognitive function of mice.Neuron morphology was detected by Nissl staining.Immunofluorescence histochemical staining was used to detect the expression of phosphorylated dynamin-related protein 1(p-Drp1)and mitochondrial fusion 1((Mfn1).Western blot analysis was used to detect the expression ROCK2,cleaved-caspase-3(c-caspase-3),B-cell lymphoma 2(Bcl2),Bcl2-related protein X(BAX),p-Drpl,mitochondrial fission 1(Fis1),optic atrophy 1(OPA1),Mfn1 and Mfn2.Results Compared with AD group mice,the expression of ROCK2 in shROCK2 group mice was significantly reduced;the cognitive function was significantly improved with the number of neurons in the hippocampal CA3 and DG areas increasing,and nissl bodies were deeply stained;the expression of c-caspase-3 and BAX was decreased,while the expression of Bcl2 was increased;the expression of mitochondrial division related proteins p-Drpl and Fis1 were decreased,while the expression of mitochondrial fusion-related proteins OPA1,Mfn1 and Mfn2 were increased.Conclusion Knock-down of ROCK2 gene can significantly improve the cognitive function and inhibit the apoptosis of nerve cells of APP/PS1 mice.The mechanism may be related to promoting mitochondrial fusion and inhibiting its division.

关 键 词:阿尔茨海默病 淀粉样前体蛋白/早老素1(APP/PS1)小鼠 Rho相关螺旋卷曲激酶2(ROCK2) 认知障碍 凋亡 线粒体动力学 

分 类 号:R392-33[医药卫生—免疫学] R749.16[医药卫生—基础医学] Q25[生物学—细胞生物学]

 

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