CCR3特异性拮抗剂GW766994在阿尔茨海默病发病机制中的作用研究  

Role of CCR3-specific antagonist GW766994 in the pathogenesis of Alzheimer′s disease

作　　者：隋轶[1] 徐冰[1] 任莉[1] 董春瑶[1] 张尧[1] SUI Yi;XU Bing;REN Li;DONG Chun-yao;ZHANG Yao(Department of Neurology,Shenyang First People's Hospital,Shenyang Medical College Affiliated Shenyang Brain Hospital,Shenyang Brian Institute,Shenyang 110041,China)

机构地区：[1]沈阳市第一人民医院神经内科,沈阳医学院附属沈阳脑科医院,沈阳市脑病研究所,沈阳110041

出　　处：《实用药物与临床》2019年第3期240-245,共6页Practical Pharmacy and Clinical Remedies

基　　金：辽宁省自然科学基金课题(2015020547);中国博士后科学基金(2015M581375);沈阳市科技人才应用技术研究项目(18-014-4-51)

摘　　要：目的观察特异性CCR3拮抗剂GW766994是否通过拮抗趋化因子CCL11的作用影响阿尔茨海默病(AD)的病理变化。方法在原代海马神经元培养物中应用Western blot、ELISA和体视学细胞计数等方法,分别测定CDK5、GSK3β、磷酸化tau蛋白和可溶性Aβ的水平以及树突交叉和成熟树突脊的数量。结果 CCL11的受体CCR3由海马神经元表达,用CCL11处理原代海马神经元培养物(体外14 d,14 DIV),导致细胞周期蛋白依赖性激酶5(CDK 5)和糖原合酶激酶-3β(GSK 3β)的激活,并与多个位点的tau蛋白磷酸化升高有关。CCL11培养也诱导体外培养的海马神经元培养物中Aβ的产生和树突棘的缺失。所有这些作用都被CCR3特异性拮抗剂GW766994所阻断。结论体外海马神经元中一系列AD的病理变化均可由CCL11处理诱导,并能被CCR3特异性拮抗剂GW766994所阻断。GW766994作为一种特异性CCR3拮抗剂,显著逆转了上述过程,为AD治疗提供了可能的靶点。Objective To observe whether GW766994,a specific CCR3 antagonist,plays a role in the pathogenesis of Alzheimer's disease through chemokine CCL11 treatment.Methods In the cell culture treated with CCL11(10 nmol/L),we employed the methods such as Western blot,ELISA,immunohistochemistry and unbiased stereological counting to quantitatively examine the level of CDK 5,GSK 3β,phosphorylated tau,soluble Aβ,dendritic crossings and dendritic spines.Results CCR3 was expressed by cultured hippocampal neurons.In primary hippocampal neuronal culture,CCL11 treatment resulted in the activation of CDK 5 and GSK 3β as well as increased phosphorylated tau at multiple sites.CCL11 treatment also induced the production of β amyloid and the loss of dendritic spines in the hippocampal neuronal cultures.All these deleterious effects were blocked or reversed by the addition of GW766994.Conclusion CCL11 induced deleterious effects in hippocampal neuronal culture in vitro by activating CCR 3,while GW766994 blocked these effects partially or completely by antagonizing CCR 3.

关 键 词：阿尔茨海默病 趋化因子 Β淀粉样蛋白 TAU蛋白 CCL11 

分 类 号：R96[医药卫生—药理学]