Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
Pharmacol Res. 2022 Apr;178:106153. doi: 10.1016/j.phrs.2022.106153. Epub 2022 Mar 4.
Alzheimer's disease (AD) pathogenesis is known to involve a dysregulation of microRNA expression, and these intricate transcriptional cascades between multiple pathological manifestations affect brain homeostasis. Previous studies have revealed that miR-30a-5p participates in neuronal damage and is upregulated in amyloid beta-peptide (Aβ)-induced models. However, its involvement in cognition dysfunction and the AD pathogenic process remains unclear. In the present study, we investigated the mechanisms underlying miR-30a-5p involvement in AD, and its potential as a therapeutic target. Our results reveal that miR-30a-5p was substantially upregulated during the pathological progression of AD, presenting as an increased level in the cortex and hippocampus of APP/PS1 and five familial AD mice, AD cells, and the plasma of AD patients. miR-30a-5p overexpression also induced neuronal injury and apoptosis in AD cells. Mechanistically, miR-30a-5p negatively regulated ADAM10 and SIRT1 by directly binding to their 3'-untranslated regions. A possible association between SIRT1 and ADAM10 was observed via their rescue of miR-30a-5p-induced RARβ downregulation. Interestingly, miR-30a-5p was observed to inhibit the nonamyloidogenic pathway by down regulating ADAM10 and SIRT1, thus promoting Aβ overproduction. In APP/PS1 mice, knockdown of miR-30a-5p ameliorated cognitive dysfunctions and neurodegenerative changes, suppressed Aβ accumulation, and inhibited Aβ generation by enhancing the nonamyloidogenic pathway via upregulation of ADAM10 and SIRT1. However, these improvements were blocked by ADAM10 and SIRT1 silencing. In conclusion, the present study implicates dysregulation of the miR-30a-5p/ ADAM10/ SIRT1 pathway as a critical mediator of AD pathogenesis, highlighting the importance of epigenetics and identifying novel therapeutic targets in the nonamyloidogenic pathway.
阿尔茨海默病（AD）的发病机制已知涉及 microRNA 表达的失调，这些复杂的转录级联反应在多种病理表现之间相互影响，影响大脑的内稳态。先前的研究表明，miR-30a-5p 参与神经元损伤，并且在淀粉样β肽（Aβ）诱导的模型中上调。然而，其在认知功能障碍和 AD 发病机制中的作用尚不清楚。在本研究中，我们研究了 miR-30a-5p 参与 AD 的机制及其作为治疗靶点的潜力。我们的结果表明，miR-30a-5p 在 AD 的病理进展过程中显著上调，在 APP/PS1 和五种家族性 AD 小鼠、AD 细胞和 AD 患者的血浆中，皮质和海马中均呈增加水平。miR-30a-5p 的过表达也诱导 AD 细胞中的神经元损伤和凋亡。机制上，miR-30a-5p 通过直接与其 3'-UTR 结合来负调控 ADAM10 和 SIRT1。通过它们对 miR-30a-5p 诱导的 RARβ 下调的挽救，观察到 SIRT1 和 ADAM10 之间可能存在关联。有趣的是，miR-30a-5p 通过下调 ADAM10 和 SIRT1 抑制非淀粉样生成途径，从而促进 Aβ 的过度产生。在 APP/PS1 小鼠中，miR-30a-5p 的敲低改善了认知功能障碍和神经退行性变化，抑制了 Aβ 的积累，并通过增强非淀粉样生成途径来抑制 Aβ 的产生，从而通过上调 ADAM10 和 SIRT1。然而，这些改善被 ADAM10 和 SIRT1 的沉默所阻断。总之，本研究表明，miR-30a-5p/ADAM10/SIRT1 通路的失调是 AD 发病机制的关键介质，强调了表观遗传学的重要性，并确定了非淀粉样生成途径中的新治疗靶点。
