中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (10): 2099-2108.doi: 10.4103/1673-5374.308104

• 原著:退行性病与再生 • 上一篇    下一篇

阿尔茨海默病转基因模型小鼠大脑皮质微小RNA和信使RNA：RNA测序

  

  • 出版日期:2021-10-15 发布日期:2021-03-19
  • 基金资助:

    中国国家自然科学基金项目（面上项目）（81673411）；国家自然科学基金项目联合项目（U1803281）；中国医学科学院青年医学人才奖励计划（2018RC350013）；中国医学科学院医学创新计划（2017-I2M-1-016）

MicroRNA and mRNA profiling of cerebral cortex in a transgenic mouse model of Alzheimer’s disease by RNA sequencing

Li Zeng1, #, Hai-Lun Jiang1, #, Ghulam Md Ashraf2, 3, Zhuo-Rong Li1, *, Rui Liu1, *   

  1. 1Organic Chemistry and Function Laboratory, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
  • Online:2021-10-15 Published:2021-03-19
  • Contact: Rui Liu, PhD, liurui@imb.pumc.edu.cn; Zhuo-Rong Li, MD, lizhourong@imb.pumc.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China (General Program), No. 81673411; the United Fund Project of National Natural Science Foundation of China, No. U1803281; Young Medical Talents Award Project of Chinese Academy of Medical Sciences, No. 2018RC350013; and Chinese Academy of Medical Sciences Innovation Project for Medical Science, No. 2017-I2M-1-016 (all to RL).

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摘要：

作者既往研究发现阿尔茨海默病中长链非编码基因是基于微小RNA（miRNA）与信使RNA（mRNA）募集导致的内源性基因紊乱，并提出miR-200a-3p等代表性miRNA具有介导认知损伤及作为新型生物标志物的意义。在此期基础上，此次实验利用经典的淀粉样蛋白前体蛋白和早老素1双转基因阿尔茨海默病小鼠模型，对其大脑皮质进行RNA测序和整合分析，探索miRNA和mRNA的异常表达及阿尔茨海默病基于表观遗传层面的发病机制。（1）共发现了129个异常表达的mRNA和68个异常表达的miRNA，其中8个下调的miRNA和7个上调的miRNA似乎是潜在的生物标志物和治疗靶点，而且这些miRNA主要参与主要涉及丝裂原活化激酶蛋白、磷脂酰肌醇3-激酶蛋白激酶B、雷帕霉素激酶的靶点、FoxO和自噬信号通路；（2）构建了失调miRNA和与阿尔茨海默病进展相关的靶基因的miRNA-mRNA网络；（3）这些miRNA和mRNA可能成为早期诊断和预防阿尔茨海默病的潜在生物标志物和治疗靶点，亦可为miRNA和mRNA在阿尔茨海默病中的潜在作用提供了新的视角。实验于2019年9月6日经中国医学科学院北京协和医学院医药生物技术研究所伦理委员会批准，批准号IMB-201909-D6。

https://orcid.org/0000-0001-8834-8885 (Li Zeng); https://orcid.org/0000-0001-6684-8870 (Hai-Lun Jiang); https://orcid.org/0000-0002-9820-2078 (Ghulam Md Ashraf); https://orcid.org/0000-0001-5748-7444 (Zhuo-Rong Li); https://orcid.org/0000-0002-8578-0733 (Rui Liu)

关键词:

阿尔茨海默病, 生物标志物, 大脑皮质, 基因本体论, 细胞内神经原纤维缠结, 微管相关蛋白τ, miRNA-mRNA网络, 早老素1, 高通量测序, 3'非翻译区

Abstract: In a previous study, we found that long non-coding genes in Alzheimer’s disease (AD) are a result of endogenous gene disorders caused by the recruitment of microRNA (miRNA) and mRNA, and that miR-200a-3p and other representative miRNAs can mediate cognitive impairment and thus serve as new biomarkers for AD. In this study, we investigated the abnormal expression of miRNA and mRNA and the pathogenesis of AD at the epigenetic level. To this aim, we performed RNA sequencing and an integrative analysis of the cerebral cortex of the widely used amyloid precursor protein and presenilin-1 double transgenic mouse model of AD. Overall, 129 mRNAs and 68 miRNAs were aberrantly expressed. Among these, eight down-regulated miRNAs and seven up-regulated miRNAs appeared as promising noninvasive biomarkers and therapeutic targets. The main enriched signaling pathways involved mitogen-activated kinase protein, phosphatidylinositol 3-kinase-protein kinase B, mechanistic target of rapamycin kinase, forkhead box O, and autophagy. An miRNA-mRNA network between dysregulated miRNAs and corresponding target genes connected with AD progression was also constructed. These miRNAs and mRNAs are potential biomarkers and therapeutic targets for new treatment strategies, early diagnosis, and prevention of AD. The present results provide a novel perspective on the role of miRNAs and mRNAs in AD. This study was approved by the Experimental Animal Care and Use Committee of Institute of Medicinal Biotechnology of Beijing, China (approval No. IMB-201909-D6) on September 6, 2019.

Key words: 3?-untranslated region, Alzheimer’s disease, biomarker, cerebral cortex, Gene Ontology, high-throughput sequencing, intracellular neurofibrillary tangles, microtubule-associated protein-τ, miRNA-mRNA network, presenilin 1

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