基于综合生物信息学分析鉴定维持认知正常脑老化的关键生物标志物和通路
Identification of Key Biomarkers and Pathways for Maintaining Cognitively Normal Brain Aging Based on Integrated Bioinformatics Analysis.
作者信息
Xu Jinling, Zhou Hui, Xiang Guangda
机构信息
The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
Department of Endocrinology, General Hospital of Central Theater Command, Wuhan, China.
出版信息
Front Aging Neurosci. 2022 Mar 9;14:833402. doi: 10.3389/fnagi.2022.833402. eCollection 2022.
BACKGROUND
Given the arrival of the aging population has caused a series of social and economic problems, we aimed to explore the key genes underlying cognitively normal brain aging and its potential molecular mechanisms.
METHODS
GSE11882 was downloaded from Gene Expression Omnibus (GEO). The data from different brain regions were divided into aged and young groups for analysis. Co-expressed differentially expressed genes (DEGs) were screened. Functional analysis, protein-protein interaction (PPI) network, microRNA (miRNA)-gene, and transcription factor (TF)-gene networks were performed to identify hub genes and related molecular mechanisms. AlzData database was used to elucidate the expression of DEGs and hub genes in the aging brain. Animal studies were conducted to validate the hub genes.
RESULTS
Co-expressed DEGs contained 7 upregulated and 87 downregulated genes. The enrichment analysis indicated DEGs were mainly involved in biological processes and pathways related to immune-inflammatory responses. From the PPI network, 10 hub genes were identified: C1QC, C1QA, C1QB, CD163, FCER1G, VSIG4, CD93, CD14, VWF, and CD44. CD44 and CD93 were the most targeted DEGs in the miRNA-gene network, and TIMP1, HLA-DRA, VWF, and FGF2 were the top four targeted DEGs in the TF-gene network. In AlzData database, the levels of CD44, CD93, and CD163 in patients with Alzheimer's disease (AD) were significantly increased than those in normal controls. Meanwhile, in the brain tissues of cognitively normal mice, the expression of CD44, CD93, and CD163 in the aged group was significantly lower than those in the young group.
CONCLUSION
The underlying molecular mechanisms for maintaining healthy brain aging are related to the decline of immune-inflammatory responses. CD44, CD93, and CD 163 are considered as potential biomarkers. This study provides more molecular evidence for maintaining cognitively normal brain aging.
背景
鉴于老龄化人口的到来引发了一系列社会和经济问题，我们旨在探索认知功能正常的大脑衰老背后的关键基因及其潜在分子机制。
方法
从基因表达综合数据库（GEO）下载GSE11882。将来自不同脑区的数据分为老年组和青年组进行分析。筛选共表达的差异表达基因（DEG）。进行功能分析、蛋白质-蛋白质相互作用（PPI）网络、微小RNA（miRNA）-基因和转录因子（TF）-基因网络分析，以鉴定枢纽基因和相关分子机制。利用AlzData数据库阐明衰老大脑中DEG和枢纽基因的表达情况。进行动物研究以验证枢纽基因。
结果
共表达的DEG包括7个上调基因和87个下调基因。富集分析表明，DEG主要参与与免疫炎症反应相关的生物学过程和通路。从PPI网络中鉴定出10个枢纽基因：C1QC、C1QA、C1QB、CD163、FCER1G、VSIG4、CD93、CD14、VWF和CD44。CD44和CD93是miRNA-基因网络中靶向性最高的DEG，而TIMP1、HLA-DRA、VWF和FGF2是TF-基因网络中靶向性最高的前四个DEG。在AlzData数据库中，阿尔茨海默病（AD）患者的CD44、CD93和CD163水平显著高于正常对照组。同时，在认知功能正常的小鼠脑组织中，老年组CD44、CD93和CD163的表达明显低于青年组。
结论
维持健康大脑衰老的潜在分子机制与免疫炎症反应的下降有关。CD44、CD93和CD163被认为是潜在的生物标志物。本研究为维持认知功能正常的大脑衰老提供了更多分子证据。
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