microRNA⁃9⁃5p通过抑制Tau磷酸化参与阿尔茨海默病的机制  被引量:2

microRNA⁃9⁃5p involves in Alzheimer′s disease by inhibiting Tau phosphorylation

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作  者:郝婧雯 邓炎尧 谢君 万奇 HAO Jingwen;DENG Yanyao;XIE Jun;WAN Qi(Department of Neurology,Changsha First Hospital,Changsha 410000,China)

机构地区:[1]长沙市第一医院神经内科,长沙410000

出  处:《实用医学杂志》2022年第18期2296-2302,共7页The Journal of Practical Medicine

基  金:湖南创新型省份建设专项(编号:2019JJ80066)。

摘  要:目的探讨microRNA⁃9⁃5p(miR⁃9⁃5p)在阿尔茨海默病(AD)小鼠模型海马和血浆中表达情况及其过表达对Tau磷酸化的影响。方法选择雄性APPswe/PS1dE9(APP/PS1)转基因小鼠和WT C57BL/6(WT)小鼠作为研究对象。将APP/PS1小鼠和WT小鼠各随机分为3组小鼠随机分为3组:Lv⁃WT组、Lv⁃con组和Lv⁃miR⁃9⁃5p组,每组18只。将Lv⁃miR⁃9⁃5p(4×105转导单位[TU])或Lv⁃con(4×105 TU)缓慢注射到Lv⁃miR⁃9⁃5p组和Lv⁃con组的双侧海马中。注射后30 d进行行为测试或电生理实验。通过微阵列和定量实时PCR分析miRNA表达,免疫印迹和免疫荧光分析AT8蛋白表达。结果与Lv⁃con组小鼠相比,Lv⁃miR⁃9⁃5p组小鼠的辨别指数、关联条件恐惧停止、暗示条件恐惧停止、跨平台次数和目标象限时间均显著增加(P<0.05),跨平台时间显著降低(P<0.05)。Lv⁃miR⁃9⁃5p组小鼠海马中的突触棘密度、蘑菇刺的百分比较Lv⁃con组显著增加(P<0.05),并且Lv⁃miR⁃9⁃5p组小鼠表现出更高的长期增强幅度。与Lv⁃WT组相比,Lv⁃con组小鼠海马中AT8水平及AT8和γH2AX共定位数量显著升高(P<0.05)。Lv⁃miR⁃9⁃5p组小鼠海马中AT8较Lv⁃con组显著降低(P<0.05)。结论miR⁃9⁃5p在AD发病机制中发挥有益作用,其保护机制涉及减少异常Tau磷酸化和DNA损伤。Objective To investigate the expression of microRNA⁃9⁃5p(miR⁃9⁃5p)in the hippocampus and plasma of a mouse model of Alzheimer′s disease(AD),and the effect of its overexpression on Tau pathology.Methods Male APPswe/PS1dE9(APP/PS1)transgenic mice and WT C57BL/6(WT)mice were selected as research subjects,and then they were randomly divided into 3 groups:Lv⁃WT group,Lv⁃con group and Lv⁃miR⁃9⁃5p group,with 18 mice in each group.Lv⁃miR⁃9⁃5p(4×105 TU)or Lv⁃con(4×105 TU)was slowly injected into bilateral hippocampus of the mice in the Lv⁃miR⁃9⁃5p group and Lv⁃con group.The behavior tests or electro⁃physiology experiments were performed 30 days after the injection.miRNA expression and AT8 protein expression were analyzed by microarray and quantitative real⁃time PCR and immunoblotting and immunofluorescence,respec⁃tively.Results Compared with the Lv⁃con group,the discrimination index,contextual fear cessation,cue condi⁃tioned fear cessation,cross⁃platform times and target quadrant time were significantly increased(P<0.05),and cross⁃platform time was significantly decreased in the Lv⁃miR⁃9⁃5p group(P<0.05).The density of synaptic spines and the percentage of mushroom spines in the hippocampus of mice in the Lv⁃miR⁃9⁃5p group were signifi⁃cantly higher than those in the Lv⁃con group(P<0.05),and the mice in the Lv⁃miR⁃9⁃5p group showed higher long⁃term enhancement.Compared with the Lv⁃WT group,the level of AT8 and the co⁃localization amount of AT8 andγH2AX in the hippocampus of mice in the Lv⁃con group were significantly increased(P<0.05).The amount of AT8 in the Lv⁃miR⁃9⁃5p group was significantly reduced than that in the Lv⁃con group(P<0.05).Conclusion miR⁃9⁃5p plays a beneficial role in AD pathogenesis by reducing aberrant Tau phosphorylation and DNA damage.

关 键 词:microRNA⁃9⁃5p 阿尔茨海默病 小鼠 TAU磷酸化 

分 类 号:R741.02[医药卫生—神经病学与精神病学]

 

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