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

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. Twelve APP/PS1 mice were grouped by age (1 month, 3 months, 6 months, and 9 months), and the same grouping was applied to the twelve corresponding WT control mice. Each age group included three mice (two female and one male).

本研究从表观遗传学层面，探究了阿尔茨海默病（AD, Alzheimer's Disease）模型中微小RNA（miRNA, microRNA）与信使RNA（mRNA, messenger RNA）的异常表达情况及疾病发病机制。为此，本研究针对当前广泛使用的阿尔茨海默病淀粉样前体蛋白（amyloid precursor protein, APP）与早老素1（presenilin-1, PS1）双转基因小鼠模型的大脑皮层组织，开展了RNA测序及整合分析。经统计，共计129条mRNA与68条miRNA呈现异常表达。其中，8条表达下调的miRNA与7条表达上调的miRNA展现出成为非侵入性生物标志物及治疗靶点的良好潜力。显著富集的信号通路主要包括丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）、磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）、雷帕霉素靶蛋白激酶（mechanistic target of rapamycin kinase, mTOR）、叉头框转录因子O（FoxO）以及自噬通路。本研究还构建了异常表达miRNA与对应靶基因之间的调控网络，该网络与AD进展密切相关。上述异常表达的miRNA与mRNA可作为潜在生物标志物与治疗靶点，为阿尔茨海默病的新型治疗策略开发、早期诊断及疾病预防提供全新方向。本研究结果为阐明miRNA与mRNA在AD中的作用提供了崭新视角。本研究将12只APP/PS1双转基因小鼠按月龄分为4组（1月龄、3月龄、6月龄及9月龄），同时设置12只对应月龄的野生型（WT, wild type）对照小鼠并采用相同分组方式。每个月龄组均包含3只小鼠（2只雌性与1只雄性）。