Ye Xiaoyang, Luo Hongxue, Chen Yan, Wu Qi, Xiong Yi, Zhu Jinyong, Diao Yarui, Wu Zhenguo, Miao Jianting, Wan Jun
Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center , Shenzhen , China.
Division of Life Science, The Hong Kong University of Science and Technology , Hong Kong , China.
Front Aging Neurosci. 2015 Nov 18;7:210. doi: 10.3389/fnagi.2015.00210. eCollection 2015.
Alzheimer's disease (AD) is the most common cause of dementia. Amyloid β (Abeta, Aβ) deposition and intracellular tangles are the pathological hallmarks of AD. MicroRNAs (miRNAs) are small non-coding RNAs, which have been found to play very important roles, and have the potential to serve as diagnostic markers during neuronal pathogenesis. In this study, we aimed to determine the roles of miR-99b-5p and miR-100-5p in Aβ-induced neuronal pathologies. We detected the expression levels of miR-99b-5p and miR-100-5p in the brains of APPswe/PS1ΔE9 double-transgenic mice (APP/PS1 mice) at different age stages and found that both miRNAs were decreased at early stages while increased at late stages of APP/PS1 mice when compared with the age-matched wild type (WT) mice. Similar phenomenon was also observed in Aβ-treated cultured cells. We also confirmed that mammalian target of rapamycin (mTOR) is one of the targets of miR-99b-5p/100-5p, which is consistent with previous studies in cancer. MiR-99b-5p/100-5p has been found to promote cell apoptosis with the Aβ treatment. This effect may be induced via the mTOR pathway. In our study, we find both miR-99b-5p and miR-100-5p affect neuron survival by targeting mTOR. We also speculate that dynamic change of miR-99b-5p/100-5p levels during Aβ-associated pathologies might be attributed to Aβ-induced endoplasmic reticulum stress (ER stress), suggesting the potential role of the "ER stress-miRNAs-mTOR" axis in Aβ-related AD pathogenesis.
阿尔茨海默病（AD）是痴呆最常见的病因。淀粉样β蛋白（Aβ）沉积和细胞内缠结是AD的病理特征。微小RNA（miRNA）是小的非编码RNA，已发现其发挥着非常重要的作用，并且在神经元发病机制中具有作为诊断标志物的潜力。在本研究中，我们旨在确定miR-99b-5p和miR-100-5p在Aβ诱导的神经元病变中的作用。我们检测了不同年龄阶段的APPswe/PS1ΔE9双转基因小鼠（APP/PS1小鼠）大脑中miR-99b-5p和miR-100-5p的表达水平，发现与年龄匹配的野生型（WT）小鼠相比，这两种miRNA在APP/PS1小鼠的早期阶段降低而在晚期阶段升高。在Aβ处理的培养细胞中也观察到类似现象。我们还证实雷帕霉素靶蛋白（mTOR）是miR-99b-5p/100-5p的靶标之一，这与先前在癌症中的研究一致。已发现miR-99b-5p/100-5p在Aβ处理时促进细胞凋亡。这种作用可能通过mTOR途径诱导。在我们的研究中发现miR-99b-5p和miR-100-5p均通过靶向mTOR影响神经元存活。我们还推测在Aβ相关病变过程中miR-99b-5p/100-5p水平的动态变化可能归因于Aβ诱导的内质网应激（ER应激），提示“ER应激-miRNA-mTOR”轴在Aβ相关的AD发病机制中的潜在作用。
