Hu Ling, Zhang Rong, Yuan Qiong, Gao Yinping, Yang Mary Q, Zhang Chunxiang, Huang Jiankun, Sun Yufei, Yang William, Yang Jack Y, Min Zhen-Li, Cheng Jing, Deng Youping, Hu Xiamin
Department of Anesthesiology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, 430064, China.
Department of Pharmacy, College of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, Hubei Province, China.
BMC Syst Biol. 2018 Dec 14;12(Suppl 7):119. doi: 10.1186/s12918-018-0633-3.
Accumulation of amyloid β-peptide (Aβ) is implicated in the pathogenesis and development of Alzheimer's disease (AD). Neuron-enriched miRNA was aberrantly regulated and may be associated with the pathogenesis of AD. However, regarding whether miRNA is involved in the accumulation of Aβ in AD, the underlying molecule mechanism remains unclear. Therefore, we conduct a systematic identification of the promising role of miRNAs in Aβ deposition, and shed light on the molecular mechanism of target miRNAs underlying SH-SY5Y cells treated with Aβ-induced cytotoxicity.
Statistical analyses of microarray data revealed that 155 significantly upregulated and 50 significantly downregulated miRNAs were found on the basis of log2 | Fold Change | ≥ 0.585 and P < 0.05 filter condition through 2588 kinds of mature miRNA probe examined. PCR results show that the expression change trend of the selected six miRNAs (miR-6845-3p, miR-4487, miR-4534, miR-3622-3p, miR-1233-3p, miR-6760-5p) was consistent with the results of the gene chip. Notably, Aβ downregulated hsa-miR-4487 and upregulated hsa-miR-6845-3p in SH-SY5Y cell lines associated with Aβ-mediated pathophysiology. Increase of hsa-miR-4487 could inhibit cells apoptosis, and diminution of hsa-miR-6845-3p could attenuate axon damage mediated by Aβ in SH-SY5Y.
Together, these findings suggest that dysregulation of hsa-miR-4487 and hsa-miR-6845-3p contributed to the pathogenesis of AD associated with Aβ25-35 mediated by triggering cell apoptosis and synaptic dysfunction. It might be beneficial to understand the pathogenesis and development of clinical diagnosis and treatment of AD. Further, our well-designed validation studies will test the miRNAs signature as a prognostication tool associated with clinical outcomes in AD.
淀粉样β肽（Aβ）的积累与阿尔茨海默病（AD）的发病机制和发展有关。富含神经元的微小RNA（miRNA）受到异常调节，可能与AD的发病机制有关。然而，关于miRNA是否参与AD中Aβ的积累，其潜在的分子机制仍不清楚。因此，我们系统地鉴定了miRNA在Aβ沉积中的潜在作用，并阐明了在Aβ诱导细胞毒性处理的SH-SY5Y细胞中，靶miRNA的分子机制。
通过对2588种成熟miRNA探针进行检测，基于log2 |倍数变化|≥0.585和P<0.05的筛选条件，对微阵列数据进行统计分析，发现155种miRNA显著上调，50种miRNA显著下调。聚合酶链反应（PCR）结果显示，所选的6种miRNA（miR-6845-3p、miR-4487、miR-4534、miR-3622-3p、miR-1233-3p、miR-6760-5p）的表达变化趋势与基因芯片结果一致。值得注意的是，在与Aβ介导的病理生理学相关的SH-SY5Y细胞系中，Aβ下调了hsa-miR-4487并上调了hsa-miR-6845-3p。hsa-miR-4487的增加可抑制细胞凋亡，而hsa-miR-6845-3p的减少可减轻Aβ介导的SH-SY5Y细胞轴突损伤。
总之，这些发现表明，hsa-miR-4487和hsa-miR-6845-3p的失调通过触发细胞凋亡和突触功能障碍，导致了与Aβ25-35介导相关的AD发病机制。这可能有助于理解AD临床诊断和治疗的发病机制及发展。此外，我们精心设计的验证研究将测试miRNA特征作为与AD临床结果相关的预后工具。
