Immune abnormalities and differential gene expression in the hippocampus and peripheral blood of patients with Alzheimer's disease.
Immune abnormalities and differential gene expression in the hippocampus and peripheral blood of patients with Alzheimer's disease.
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DOI：
10.21037/atm-21-4974
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发表时间：
2022-01
影响因子：
--
通讯作者：
Chen M
中科院分区：
文献类型：
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作者：
Wang X;Wang D;Su F;Li C;Chen M
尽管进行了几十年的研究，但阿尔茨海默病(AD)的确切发病机制尚未阐明。本研究旨在研究外周血细胞和海马区组织中新的诊断生物标志物，以及AD记忆障碍的发病机制。与AD相关的基因芯片数据，包括海马区样本(GSE1297和GSE5281)和外周血单个核细胞(PBMC)(GSE63060和GSE63061)，这些数据来自基因表达总集(GEO)数据库。通过对基因重新注释和批量归一化后的多个基因表达谱的综合分析，筛选出AD和正常衰老样本之间的差异表达基因(Deg)。基因本体论(GO)和京都基因和基因组百科全书(KEGG)途径被用来分析HUB基因和寻找与AD相关的潜在生物标志物。构建了蛋白质-蛋白质相互作用(PPI)网络图以可视化可能基因之间的相关性。为了研究炎症在AD发病机制中的作用，建立了CiberSort算法，以探索PBMC的渗透模式。生物信息学分析表明，当AD患者与正常老年人比较时，海马区样本中有1261度，外周血单核细胞中有290度。我们选择了28个在海马区和外周血单核细胞中共表达的基因。对差异基因的功能分析表明，它们主要参与神经元死亡、免疫反应和线粒体功能。免疫细胞浸润模式显示AD患者外周血中幼稚的CD4+T细胞、静息自然杀伤细胞、M0巨噬细胞和活化的肥大细胞水平较高，而静息记忆CD4+T细胞水平较低。海马体和外周血单核细胞中存在的关键基因变化高度表明它们作为AD生物标记物的实用性。此外，根据我们目前的结果，免疫异常可能在AD的病理生理学中起重要作用。当患者表现出这些外周血液免疫异常时，他们可能被认为是发展为AD的高危人群。
Despite decades of research, no precise mechanisms of Alzheimer’s disease (AD) development have been elucidated. This study aimed to investigate novel diagnostic biomarkers in both peripheral blood cells and hippocampus tissue, and the pathogenesis of memory impairment in AD. mRNA microarray data, including hippocampus samples (GSE1297 and GSE5281) and peripheral blood mononuclear cells (PBMCs) (GSE63060 and GSE63061), associated with AD were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between AD and normal-aging samples were screened through a comprehensive analysis of multiple gene expression spectra after gene reannotation and batch normalization. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were used to analyze hub genes and to discover potential biomarkers related to AD. Protein-protein interaction (PPI) network maps were constructed to visualize the correlation between possible genes. The CIBERSORT algorithm was built to explore the patterns of PBMC infiltration to investigate the role of inflammation in the pathogenesis of AD. The bioinformatics analysis indicated 1,261 DEGs in the hippocampal samples and 290 in PBMCs when comparing patients with AD with normal-aging individuals. We selected 28 genes co-expressed in the hippocampus and PBMCs. A functional analysis of differential genes revealed that they were primarily involved in neuronal death, immune response, and mitochondrial function. Further, immune cell infiltration patterns demonstrated that the levels of naive CD4+ T cells, resting natural killer cells, M0 macrophages, and activated mast cells were higher in the peripheral blood of patients with AD, while resting memory CD4+ T cells were significantly lower. The key gene changes present in both the hippocampus and PBMCs highly suggest their utility as an AD biomarker. In addition, according to our present results, immune abnormalities may have an important role in AD pathophysiology. When patients display these peripheral blood immune abnormalities, they may be recognized as being at high risk of developing AD.