Guangdong-Hongkong-Macau Institute of CNS Regeneration, Guangdong Key Laboratory of Nonhuman Primate Models of Human Diseases, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou, 510632, China.
The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
Mol Neurobiol. 2023 May;60(5):2426-2441. doi: 10.1007/s12035-023-03224-y. Epub 2023 Jan 19.
Alzheimer's disease (AD) pathogenesis feature progressive neurodegeneration, amyloid-β plaque formation, and neurofibrillary tangles. Ample evidence has indicated the involvement of epigenetic pathways in AD pathogenesis. Here, we show that the expression of microRNA 650 (miR-650) is altered in brains from AD patients. Furthermore, we found that the processing of primary miR-650 to mature miR-650 is misregulated. Bioinformatic analysis predicted that miR-650 targets the expression of three AD-associated components: Apolipoprotein E (APOE), Presenilin 1 (PSEN1), and Cyclin-Dependent Kinase 5 (CDK5), and we have experimentally confirmed that miR-650 is able to significantly reduce the expression of APOE, PSEN1, and CDK5 in vitro. Importantly, the overexpression of miR-650 was further shown to significantly alter the CDK5 level and ameliorate AD pathologies in APP-PSEN1 transgenic mice. Overall, our results indicate that miR-650 influences AD pathogenesis through regulation of CDK5.
阿尔茨海默病（AD）的发病特征为进行性神经退行性变、淀粉样β斑块形成和神经纤维缠结。大量证据表明表观遗传途径参与 AD 的发病机制。在这里，我们显示 microRNA 650（miR-650）的表达在 AD 患者的大脑中发生改变。此外，我们发现初级 miR-650 加工为成熟 miR-650 的过程受到错误调控。生物信息学分析预测 miR-650 靶向三种与 AD 相关的成分的表达：载脂蛋白 E（APOE）、早老素 1（PSEN1）和周期蛋白依赖性激酶 5（CDK5），我们已经通过实验证实 miR-650 能够显著降低 APOE、PSEN1 和 CDK5 的体外表达。重要的是，miR-650 的过表达进一步显示可显著改变 CDK5 水平并改善 APP-PSEN1 转基因小鼠的 AD 病理学。总的来说，我们的结果表明 miR-650 通过调节 CDK5 影响 AD 的发病机制。
