miR-125b promotes tau phosphorylation by targeting the neural cell adhesion molecule in neuropathological progression
miR-125b promotes tau phosphorylation by targeting the neural cell adhesion molecule in neuropathological progression
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miR-125b 通过靶向神经病理进展中的神经细胞粘附分子促进 tau 磷酸化
DOI：
10.1016/j.neurobiolaging.2018.09.011
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发表时间：
2019-01-01
影响因子：
4.2
通讯作者：
Meng, Bo
中科院分区：
文献类型：
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作者：
Zhang, Linyu;Dong, Hao;Meng, Bo
MicroRNAs是一种小的非编码rna，它不仅在转录后水平调控多种生理过程中的基因表达，而且伴随包括痴呆在内的大量疾病的发生和发展。虽然miR-125b已被证明在一些痴呆患者中异常表达，但其在病理过程中的作用仍不明确。早老素-1/2条件双敲除小鼠表现出一系列症状，包括认知和记忆受损、tau磷酸化增加、神经炎症和细胞凋亡，因此被认为是一种有用的痴呆模型。在双敲除小鼠的前额叶皮层中，miR-125b以年龄依赖的方式异常升高。我们进一步使用双荧光素酶报告实验验证了神经细胞粘附分子（NCAM）作为miR-125b的靶标。当miR-125b在神经元生长因子诱导的分化PC12细胞中过表达（OE）时，NCAM蛋白水平降低，进一步抑制了神经元生长因子诱导的糖原合成酶激酶3 β (GSK β)在Ser9位点的磷酸化，最终增加了GSK3 β活性和tau磷酸化。此外，在血清剥夺下，分化的miR-125b-OE PC12细胞中高GSK3 β活性诱导caspase-3激活增加。最后，腺相关病毒介导的miR-125b在野生型C57B/L6小鼠前额叶皮层过表达导致树突棘密度降低。此外，与体外数据相似，证实GSK3 β活性升高和tau蛋白过度磷酸化。综上所述，我们的研究结果揭示了miR-125b对NCAM的直接调控，从而导致对下游GSK3 β活性和tau磷酸化的进一步影响，并可能有助于神经病理进展中神经原纤维缠结的产生。(C) 2018爱思唯尔公司版权所有。
MicroRNAs, small noncoding RNAs, not only regulate gene expression at the post-transcriptional level in a variety of physiological processes but also accompany the initiation and progression of a vast number of diseases, including dementia. While miR-125b has been shown to be aberrantly expressed in some dementia patients, its role in the pathological process remains ambiguous. Presenilin-1/2 conditional double knockout mice exhibit a range of symptoms, including impaired cognition and memory, increased tau phosphorylation, neuroinflammation, and apoptosis, and are therefore regarded as a useful dementia model. In the prefrontal cortices of double knockout mice, miR-125b was found to be abnormally increased in an age-dependent manner. We further verified the neural cell adhesion molecule (NCAM) as an miR-125b target using the dual luciferase reporter assay. The NCAM protein level was decreased when miR-125b was overexpressed (OE) in neuronal growth factor-induced differentiated PC12 cells, which further inhibited the neuronal growth factor-induced phosphorylation of glycogen synthase kinase 3 beta (GSK beta) at the Ser9 site and ultimately increased the GSK3 beta activity and tau phosphorylation. Moreover, on serum deprivation, high GSK3 beta activity in differentiated miR-125b-OE PC12 cells induced increased caspase-3 activation. Finally, adeno-associated virus-mediated miR-125b overexpression in the prefrontal cortexes of wild-type C57B/L6 mice resulted in decreased dendritic spine density. In addition, similar to the in vitro data, elevated GSK3 beta activity and hyperphosphorylation of the tau protein were confirmed. Taken together, our findings reveal a direct regulation of miR-125b on NCAM, which leads to further effects on downstream GSK3 beta activity and tau phosphorylation and may contribute to the generation of neurofibrillary tangles in neuropathological progression. (C) 2018 Elsevier Inc. All rights reserved.