Kang Qingmei, Xiang Yue, Li Dan, Liang Jie, Zhang Xiong, Zhou Fanlin, Qiao Mengyuan, Nie Yingling, He Yurong, Cheng Jingyi, Dai Yubing, Li Yu
Department of Pathology, Chongqing Medical University, Chongqing, 400016, China.
Center for Molecular Medicine Testing, Chongqing Medical University, Chongqing, 400016, China.
Oncotarget. 2017 Apr 11;8(15):24314-24326. doi: 10.18632/oncotarget.15149.
Hyperphosphorylation of Tau forming neurofibrillary tangles has been considered as a crucial event in the pathogenesis of Alzheimer's disease (AD). MiR-124-3p belongs to microRNA (miRNA) family and was markedly decreased in AD, however, the functions of miR-124-3p in the pathogenesis of AD remain unknown. We observed that the expression of miR-124-3p was significantly decreased in N2a/APP695swe cells; and transfection of miR-124-3p mimics not only attenuated cell apoptosis and abnormal hyperphosphorylation of Tau protein without any changes of total Tau protein, but also increased expression levels of Caveolin-1, phosphoinositide 3-kinase (PI3K), phospho-Akt (Akt-Ser473)/Akt, phospho-glycogen synthase kinase-3 beta (GSK-3β-Ser9)/GSK-3β in N2a/APP695swe cells. We further found that miR-12-3p directly targeted Caveolin-1; miR-124-3p inhibited abnormal hyperphosphorylation of Tau by regulating Caveolin-1-PI3K/Akt/GSK3β pathway in AD. This study reveals that miR-124-3p may play a neuroprotective role in AD, which may provide new ideas and therapeutic targets for AD.
Tau蛋白的过度磷酸化形成神经原纤维缠结被认为是阿尔茨海默病（AD）发病机制中的关键事件。MiR-124-3p属于微小RNA（miRNA）家族，在AD中显著降低，然而，miR-124-3p在AD发病机制中的作用仍不清楚。我们观察到miR-124-3p在N2a/APP695swe细胞中的表达显著降低；转染miR-124-3p模拟物不仅减弱了细胞凋亡和Tau蛋白的异常过度磷酸化，而总Tau蛋白没有任何变化，还增加了N2a/APP695swe细胞中小窝蛋白-1、磷酸肌醇3激酶（PI3K）、磷酸化Akt（Akt-Ser473）/Akt、磷酸化糖原合酶激酶-3β（GSK-3β-Ser9）/GSK-3β的表达水平。我们进一步发现miR-12-3p直接靶向小窝蛋白-1；miR-124-3p通过调节AD中的小窝蛋白-1-PI3K/Akt/GSK3β通路抑制Tau蛋白的异常过度磷酸化。本研究揭示miR-124-3p可能在AD中发挥神经保护作用，这可能为AD提供新的思路和治疗靶点。
