Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model
Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model
复制标题
鼻内给予 miR-146a Agomir 可挽救 AD 小鼠模型的病理过程和认知障碍
DOI：
10.1016/j.omtn.2019.10.002
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发表时间：
2019-12-06
影响因子：
8.8
通讯作者：
Cui, Lili
中科院分区：
文献类型：
--
作者：
Mai, Hui;Fan, Weihao;Cui, Lili
阿尔茨海默病（AD）是痴呆症最常见的原因，并且无法治愈。AD的病因和发病机制尚不完全清楚，遗传学被认为是AD发病的重要因素之一，已鉴定的易感基因可为AD发病机制提供线索，也是潜在的靶点。MicroRNA-146 a-5 p（miR-146 a）在炎症反应的调节中是众所周知的，并且miR-146 a的功能性SNP与AD风险相关。在这项研究中，使用非侵入性鼻腔给药，我们发现miR-146 a agomir（M146 AG）挽救了APP/PS1转基因小鼠的认知障碍，并减轻了AD小鼠模型的整体病理过程，包括神经炎症，胶质细胞活化，A β存款和tau蛋白磷酸化。此外，转录分析显示，除了神经炎症的影响，M146 AG可能作为一个多潜能的目标，在AD的干预。此外，Srsf 6被鉴定为miR-146 a的靶点，其可能在AD进展中起作用。总之，我们的研究支持鼻-脑通路对于microRNA（miRNAs）的脑施用是有效的和可操作的，并且miR-146 a可能是AD治疗的新的潜在靶点。
Alzheimer's disease (AD) is the most common cause of dementia and cannot be cured. The etiology and pathogenesis of AD is still not fully understood, the genetics is considered to be one of the most important factors for AD onset, and the identified susceptible genes could provide clues to the AD mechanism and also be the potential targets. MicroRNA-146a-5p (miR-146a) is well known in the regulation of the inflammatory response, and the functional SNP of miR-146a was associated with AD risk. In this study, using a noninvasive nasal administration, we discovered that a miR-146a agomir (M146AG) rescued cognitive impairment in the APP/PS1 transgenic mouse and alleviated the overall pathological process in the AD mouse model, including neuroinflammation, glia activation, A beta deposit, and tau phosphorylation in hippocampi. Furthermore, the transcriptional analysis revealed that besides the effect of neuroinflammation, M146AG may serve as a multi-potency target for intervention in AD. In addition, Srsf6 was identified as a target of miR-146a, which may play a role in AD progression. In conclusion, our study supports that the nasal-to-brain pathway is efficient and operable for the brain administration of microRNAs (miRNAs), and that miR-146a may be a new potential target for AD treatment.