Establishment and Validation of the Diagnostic Value of Oligodendrocyte-related Genes in Alzheimer's Disease.

Chen Li, Yan Chen, Yinhui Yao, Yazhen Shang
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引用次数: 0

Abstract

Background: AD is a demyelinating disease. Myelin damage initiates the pathological process of AD, resulting in abnormal synaptic function and cognitive decline. The myelin sheath formed by oligodendrocytes (OL) is a crucial component of white matter. Investigating AD from the perspective of OL may offer novel diagnostic and therapeutic perspectives.

Objectives: This study aimed to analyze the association between OL-related genes and Alzheimer's disease (AD) using bioinformatics and verify this association via molecular biology experiments.

Methods: The AD datasets were acquired from the Gene Expression Omnibus (GEO) database of NCBI. Consensus clustering was employed to determine the subtypes of AD, followed by evaluating the clinical characteristics of these subtypes. Subsequently, immune infiltration analysis of relevant genes and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify modules and hub genes associated with AD progression. The intersection of genes obtained was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. To narrow down the scope and identify OL-related genes with diagnostic potential, three machine learning algorithms were utilized. In addition, the eXtreme Sum (XSum) algorithm was used to screen small molecule drug candidates based on the connectivity map (CMAP) database. Finally, these identified genes were validated using Real-time fluorescence quantitative PCR (RT-qPCR).

Results: Among the three subtypes of AD, Cluster A and Cluster C exhibited increased levels of Braak and neurofibrillary tangles compared to Cluster B. The proportion of females was greater than that of males among the three subclasses of AD. There were no significant differences in age among the three subclasses, but significant differences in gene expression existed. Through WGCNA analysis, 108 genes were identified. Among these, 16 genes were identified as shared genes by the least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machines (SVM) algorithms, and logistic regression further determined 11 genes. The establishment of a nomogram demonstrated the significance of these 11 genes in AD. The "XSum" algorithm revealed five drugs with therapeutic potential for AD. qPCR analysis revealed the upregulation and downregulation of the highlighted genes. According to this study, 11 genes related to OL were also found to be associated with immune cell infiltration in AD patients. These genes demonstrated potential diagnostic value for AD. Additionally, we screened five small molecular drugs that exhibit potential therapeutic effects on AD.

Conclusion: This research provides a new perspective for personalized clinical management and treatment of AD.

少突胶质细胞相关基因在阿尔茨海默病诊断价值的建立与验证。
背景:AD是一种脱髓鞘疾病。髓磷脂损伤引发AD的病理过程,导致突触功能异常和认知能力下降。髓鞘由少突胶质细胞(OL)形成,是白质的重要组成部分。从OL角度研究AD可能提供新的诊断和治疗前景。目的:本研究旨在利用生物信息学分析ol相关基因与阿尔茨海默病(AD)的相关性,并通过分子生物学实验验证这种相关性。方法:AD数据集从NCBI基因表达综合数据库(Gene Expression Omnibus, GEO)获取。采用共识聚类法确定AD的亚型,然后评估这些亚型的临床特征。随后,进行相关基因的免疫浸润分析和加权基因共表达网络分析(WGCNA),以确定与AD进展相关的模块和枢纽基因。利用基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析得到的基因交集。为了缩小范围并识别具有诊断潜力的ol相关基因,使用了三种机器学习算法。此外,基于连接图(CMAP)数据库,采用极限和(XSum)算法筛选候选小分子药物。最后,使用实时荧光定量PCR (RT-qPCR)对这些鉴定的基因进行验证。结果:在AD的3个亚型中,A类和C类患者的Braak和神经原纤维缠结水平均高于b类患者。在AD的3个亚型中,女性所占比例大于男性。3个亚类在年龄上无显著差异,但在基因表达上存在显著差异。通过WGCNA分析,共鉴定出108个基因。其中,通过最小绝对收缩和选择算子(LASSO)、随机森林(RF)和支持向量机(SVM)算法鉴定出16个基因为共享基因,并通过逻辑回归进一步确定了11个基因。图的建立证明了这11个基因在AD中的重要意义。“XSum”算法揭示了5种具有治疗AD潜力的药物。qPCR分析显示高亮基因的上调和下调。本研究还发现了11个与OL相关的基因与AD患者免疫细胞浸润相关。这些基因显示了对阿尔茨海默病的潜在诊断价值。此外,我们筛选了五种对阿尔茨海默病有潜在治疗作用的小分子药物。结论:本研究为AD的个性化临床管理和治疗提供了新的视角。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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