Ye Xian-Wen, Liu Meng-Nan, Wang Xuan, Cheng Shui-Qing, Li Chun-Shuai, Bai Yu-Ying, Yang Lin-Lin, Wang Xu-Xing, Wen Jia, Xu Wen-Juan, Zhang Shu-Yan, Xu Xin-Fang, Li Xiang-Ri
Centre of TCM Processing Research, Beijing University of Chinese Medicine, Beijing, China.
Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
Front Aging Neurosci. 2023 Feb 27;15:1071391. doi: 10.3389/fnagi.2023.1071391. eCollection 2023.
Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (DM) have an increased incidence in modern society. Although more and more evidence has supported that DM is prone to AD, the interrelational mechanisms remain fully elucidated.
The primary purpose of this study is to explore the shared pathophysiological mechanisms of AD and DM.
Download the expression matrix of AD and DM from the Gene Expression Omnibus (GEO) database with sequence numbers GSE97760 and GSE95849, respectively. The common differentially expressed genes (DEGs) were identified by limma package analysis. Then we analyzed the six kinds of module analysis: gene functional annotation, protein-protein interaction (PPI) network, potential drug screening, immune cell infiltration, hub genes identification and validation, and prediction of transcription factors (TFs).
The subsequent analyses included 339 common DEGs, and the importance of immunity, hormone, cytokines, neurotransmitters, and insulin in these diseases was underscored by functional analysis. In addition, serotonergic synapse, ovarian steroidogenesis, estrogen signaling pathway, and regulation of lipolysis are closely related to both. DEGs were input into the CMap database to screen small molecule compounds with the potential to reverse AD and DM pathological functions. L-690488, exemestane, and BMS-345541 ranked top three among the screened small molecule compounds. Finally, 10 essential hub genes were identified using cytoHubba, including and . For the characteristic Aβ and Tau pathology of AD, was associated significantly positively with AD and significantly negatively with AD. In addition, we also found and significant correlations with DM phenotypes. Other datasets verified that , , and could be used as key markers of DM complicated with AD. Meanwhile, the immune cell infiltration score reflects the different cellular immune microenvironments of the two diseases.
The common pathogenesis of AD and DM was revealed in our research. These common pathways and hub genes directions for further exploration of the pathogenesis or treatment of these two diseases.
阿尔茨海默病（AD）和2型糖尿病（DM）在现代社会中的发病率呈上升趋势。尽管越来越多的证据支持DM易患AD，但其相互关联机制仍未完全阐明。
本研究的主要目的是探索AD和DM共同的病理生理机制。
分别从基因表达综合数据库（GEO）下载序列号为GSE97760和GSE95849的AD和DM的表达矩阵。通过limma软件包分析鉴定共同的差异表达基因（DEG）。然后我们进行了六种模块分析：基因功能注释、蛋白质-蛋白质相互作用（PPI）网络、潜在药物筛选、免疫细胞浸润、枢纽基因鉴定与验证以及转录因子（TF）预测。
后续分析包括339个共同的DEG，功能分析强调了免疫、激素、细胞因子、神经递质和胰岛素在这些疾病中的重要性。此外，5-羟色胺能突触、卵巢类固醇生成、雌激素信号通路和脂肪分解调节与两者密切相关。将DEG输入CMap数据库以筛选具有逆转AD和DM病理功能潜力的小分子化合物。L-690488、依西美坦和BMS-345541在筛选出的小分子化合物中排名前三。最后，使用cytoHubba鉴定出10个关键枢纽基因，包括……。对于AD的特征性淀粉样β蛋白（Aβ）和 Tau病理，……与AD呈显著正相关，……与AD呈显著负相关。此外，我们还发现……和……与DM表型有显著相关性。其他数据集验证了……、……、……和……可作为DM合并AD的关键标志物。同时，免疫细胞浸润评分反映了这两种疾病不同的细胞免疫微环境。
我们的研究揭示了AD和DM的共同发病机制。这些共同途径和枢纽基因为进一步探索这两种疾病的发病机制或治疗提供了方向。
