目的 对不同阶段阿尔茨海默病海马CA1区差异表达的基因进行生物信息学分析以探究阿尔茨海默病（Alzheimer’s disease，AD）发生的分子机制。方法 从GEO数据库获取AD早期、中期、晚期基因芯片数据，筛选3个时期都具有的显著差异表达的基因，构建蛋白与蛋白相互作用（PPI）网络，利用cytoNCA获取关键基因并进行细胞实验验证，同时分析这些关键基因参与的主要生物学过程和信号通路富集程度，以探究其分子机制。结果 从AD不同阶段的基因芯片（GSE28146)中筛选出在不同时期均出现差异表达的基因412个，使用STRING构建PPI网络关系，cytoNCA构建并结合网络拓扑分析，共筛选出关键基因12个，qPCR验证了芯片结果的准确性；GO和Pathway富集分析显示与一氧化氮合酶活性的调节、细胞凋亡、缺氧反应、神经炎症等生物学过程密切相关，主要涉及的信号通路有Rap1、Ras、NF-κB、TNF、PI3K-Akt。结论 本研究发现TNF-α、白介素1-β（IL-1β）、白介素6（IL-6）等炎症相关基因的失调可能是导致AD发生的重要因素，它们可能是防治AD的潜在生物标志物或药物靶点。
Objective To investigate the molecular mechanism of Alzheimer s Disease (AD) development by bioinformatics analysis which is based on the genome-wide expression profile in the hippocampal CA1 region of Alzheimer s disease at different stages. Methods Early-, middle- and late-onset AD gene chip data were obtained from the GEO database, and genes with significantly different expressions in the three levels were screened, the protein-protein interaction (PPI) network constructed. The key genes were obtained by cytoNCA and verified by cell experiments. Then, the major biological processes involved in these key genes and the degree of signal pathway enrichment were analyzed to explore their molecular mechanisms.Results 30 samples were obtained by mining the gene chip (GSE28146) at different stages of the GEO database, of which 8 were normal, 7 early, 8 in the middle, and 7 severe. 412 genes differentially expressed at different times were screened. A PPI network relationship of 412 genes was constructed by STRING. The differential genes were screened by cytoNCA and combined network topology analysis, and the number of this was 12. qPCR was used to verify the accuracy of the chip results, and GO and pathway enrichment methods showed that these genes were closely related to some biological processes.(e.g. the activity of Nitric oxide synthase, apoptosis, hypoxia response and neuroinflammation) and it mainly involved in Rap1 signaling pathway, Ras signaling pathway, NF-κB signaling pathway, TNF signaling pathway, PI3K-Akt signal regulation of pathways, etc.Conclusion This study found that the dysregulation of these genes which related to inflammation (eg. TNF-α, IL-1β and IL-6) may play a vital role in the development of AD, and provide the potential biomarkers or drug targets for the treatment of AD.