Systematic identification of key basement membrane related genes as potential new biomarkers in Alzheimer's disease

摘要

Objective: The study aimed to identify biomarkers associated with basement membranes (BMs)-related genes (BMGs) in Alzheimer's disease (AD) and investigate their potential role in the progression of AD pathology. Methods: Gene expression profiles were retrieved from Gene Expression Omnibus database. 222 human BMGs were collected from the relevant literature. Subsequently, the differentially expressed BMGs (DE-BMGs) were filtered, and the key DE-BMGs were identified using weighted gene correlation network analysis (WGCNA) and two machine learning algorithms. The expression levels, diagnostic values, clinical significances, enrichment analyses and regulatory networks of these candidate biomarkers were further examined. Results: A total of 44 DE-BMGs were acquired by comparing AD temporal cortex with nondemented controls. Using WGCNA and machine learning, versiscan (VCAN), tissue inhibitor of metalloproteinase 1 (TIMP1), structural maintenance of chromosome 3 (SMC3), and laminin beta 2 (LAMB2) were ultimately identified as candidate biomarkers, and they were verified in a murine model. These biomarkers had high diagnostic value (area under the curve (AUC)>0.8). The diagnostic value of the four gene combination was then evaluated in multiple databases, yielding AUCs ranging from 0.688 to 1. Furthermore, a meaningful correlation between these biomarkers and AD pathology progression was observed. Finally, comprehensive analyses involving Hallmark pathway enrichment, immune cell infiltration analysis, transcriptional regulatory, and competitive endogenous RNA networks indicated that key DE-BMGs closely correlated with oxidative stress and immune dysfunction. Conclusion: Our study comprehensively identified four candidate BMGs and their combination model that play a crucial part in the diagnosis and pathogenesis of AD.

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