Tao Ye, Han Yu, Yu Lujiao, Wang Qi, Leng Sean X, Zhang Haiyan
Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Neurology, Jinqiu Hospital of Liaoning Province, Shenyang, China.
Front Neurol. 2020 Apr 3;11:233. doi: 10.3389/fneur.2020.00233. eCollection 2020.
To elucidate the key molecules, functions, and pathways that bridge mild cognitive impairment (MCI) and Alzheimer's disease (AD), we investigated open gene expression data sets. Differential gene expression profiles were analyzed and combined with potential MCI- and AD-related gene expression profiles in public databases. Then, weighted gene co-expression network analysis was performed to identify the gene co-expression modules. One module was significantly negatively associated with MCI samples, in which gene ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that these genes were related to cytosolic ribosome, ribosomal structure, oxidative phosphorylation, AD, and metabolic pathway. The other two modules correlated significantly with AD samples, in which functional and pathway enrichment analysis revealed strong relationships of these genes with cytoplasmic ribosome, protein binding, AD, cancer, and apoptosis. In addition, we regarded the core genes in the module network closely related to MCI and AD as bridge genes and submitted them to protein interaction network analysis to screen for major pathogenic genes according to the connectivity information. Among them, small nuclear ribonucleoprotein D2 polypeptide (, ribosomal protein S3a (, S100 calcium binding protein A8 (, small nuclear ribonucleoprotein polypeptide G (, U6 snRNA-associated Sm-like protein LSm3 (, ribosomal protein S27a (, and ATP synthase F1 subunit gamma ( were not only major pathogenic genes of MCI, but also bridge genes. In addition, , thioredoxin (, proteasome 20S subunit alpha 4 (, annexin A1 (, DnaJ heat shock protein family member A1 (, and prefoldin subunit 5 ( were not only major pathogenic genes of AD, but also bridge genes. Next, we screened for differentially expressed microRNAs (miRNAs) to predict the miRNAs and transcription factors related the MCI and AD modules, respectively. The significance score of miRNAs in each module was calculated using a hypergeometric test to obtain the miRNApivot-Module interaction pair. Thirty-four bridge regulators were analyzed, among which hsa-miR-519d-3p was recognized as the bridge regulator between MCI and AD. Our study contributed to a better understanding of the pathogenic mechanisms of MCI and AD, and might lead to the development of a new strategy for clinical diagnosis and treatment.
为了阐明连接轻度认知障碍（MCI）和阿尔茨海默病（AD）的关键分子、功能及通路，我们对公开的基因表达数据集进行了研究。分析了差异基因表达谱，并将其与公共数据库中潜在的MCI和AD相关基因表达谱相结合。然后，进行加权基因共表达网络分析以识别基因共表达模块。一个模块与MCI样本显著负相关，其中基因本体功能和京都基因与基因组百科全书通路富集分析表明，这些基因与胞质核糖体、核糖体结构、氧化磷酸化、AD及代谢通路相关。另外两个模块与AD样本显著相关，其中功能和通路富集分析显示这些基因与细胞质核糖体、蛋白质结合、AD、癌症及凋亡密切相关。此外，我们将模块网络中与MCI和AD密切相关的核心基因视为桥梁基因，并将其提交至蛋白质相互作用网络分析，以根据连接信息筛选主要致病基因。其中，小核核糖核蛋白D2多肽（ ）、核糖体蛋白S3a（ ）、S100钙结合蛋白A8（ ）、小核核糖核蛋白多肽G（ ）、U6 snRNA相关Sm样蛋白LSm3（ ）、核糖体蛋白S27a（ ）及ATP合酶F1亚基γ（ ）不仅是MCI的主要致病基因，也是桥梁基因。此外， 、硫氧还蛋白（ ）、蛋白酶体20S亚基α4（ ）、膜联蛋白A1（ ）、DnaJ热休克蛋白家族成员A1（ ）及预折叠蛋白亚基5（ ）不仅是AD的主要致病基因，也是桥梁基因。接下来，我们筛选差异表达的微小RNA（miRNA），以分别预测与MCI和AD模块相关的miRNA及转录因子。使用超几何检验计算每个模块中miRNA的显著性得分，以获得miRNA-枢纽-模块相互作用对。分析了34个桥梁调节因子，其中hsa-miR-519d-3p被识别为MCI和AD之间的桥梁调节因子。我们的研究有助于更好地理解MCI和AD的致病机制，并可能为临床诊断和治疗带来新策略的发展。
