CCR3缺乏通过减少tau蛋白激酶的活化以及tau过度磷酸化促进小鼠空间记忆缺陷的改善
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摘要
目的本研究拟探讨趋化因子受体CCR3在阿尔茨海默病(AD)小鼠模型中对于tau蛋白病理的介导作用,以及对于其认知功能障碍的影响。方法采用野生型同窝(WT)、CCR3~(-/-)、APP/PS1及APP/PS1/CCR3~(-/-)三重突变小鼠,应用蛋白印迹实验检测磷酸化tau蛋白以及磷酸化tau蛋白激酶水平;应用Morris水迷宫检测小鼠空间记忆缺陷。结果 APP/PS1双转基因小鼠中的CCR3缺陷减少了tau过度磷酸化和tau激酶的活化,同时改善了APP/PS1双转基因小鼠的空间记忆缺陷(P<0.05, one-way ANOVA)。结论 CCR3缺乏可以通过减少tau蛋白激酶的活化以及tau过度磷酸化而促进APP/PS1小鼠的空间记忆缺陷的改善。CCR3可能成为治疗AD的潜在药物靶点。
Objective To investigate the role of chemokine receptor CCR3 in the pathogenesis of tau protein in Alzheimer's disease(AD) mice and its effect on cognitive impairment. Methods Western blotting was used to detect the levels of phosphorylated tau protein and phosphorylated tau protein kinase in wild-type homozygous(WT), CCR3~(-/-), APP/PS1 and APP/PS1/CCR3~(-/-)mutant mice. Morris water maze was used todetect spatial memory deficits in mice. Results CCR3 deficiency in APP/PS1 double transgenic mice reduced tau hyperphosphorylation and tau kinase activation, and improved spatial memory deficit in APP/PS1 double transgenic mice(P<0.05, one-way ANOVA). Conclusion CCR3 deficiency can promote the improvement of spatial memory deficit in APP/PS1 mice by reducing the activation of tau protein kinase and tau hyperphosphorylation. CCR3 may be a potential drug target for the treatment of AD.
Objective To investigate the role of chemokine receptor CCR3 in the pathogenesis of tau protein in Alzheimer's disease(AD) mice and its effect on cognitive impairment. Methods Western blotting was used to detect the levels of phosphorylated tau protein and phosphorylated tau protein kinase in wild-type homozygous(WT), CCR3~(-/-), APP/PS1 and APP/PS1/CCR3~(-/-)mutant mice. Morris water maze was used todetect spatial memory deficits in mice. Results CCR3 deficiency in APP/PS1 double transgenic mice reduced tau hyperphosphorylation and tau kinase activation, and improved spatial memory deficit in APP/PS1 double transgenic mice(P<0.05, one-way ANOVA). Conclusion CCR3 deficiency can promote the improvement of spatial memory deficit in APP/PS1 mice by reducing the activation of tau protein kinase and tau hyperphosphorylation. CCR3 may be a potential drug target for the treatment of AD.
引文
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[2]Villeda SA, Luo J, Mosher KI, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature,477(7362):90-94.
[3]He J, Chen Y, Farzan M, et al. CCR3 and CCR5 are co-receptors forHIV-1infectionofmicroglia.Nature(London),1997,385(6617):645-649.
[4]Ding Y, Qiao A, Wang Z, et al. Retinoic Acid Attenuates?-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer\"s Disease Transgenic Mouse Model. Journal of Neuroscience, 2008,28(45):11622-11634.