Identification of B-cell senescence-related key genes and mechanisms in Alzheimer's disease through transcriptomic sequencing combined with Mendelian randomization analysis and experimental verification

Abstract

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Currently, no treatment method can treat AD completely successfully. Objective This work seeks to uncover new genetic signatures linking B-cell senescence to AD, elucidate the immune-related pathological mechanisms of AD. Methods The GSE85426 and GSE168813 for AD were obtained from public databases. Differential analysis of expression matrix in GSE85426 was conducted to screen differentially expressed genes (DEGs), WGCNA was explored to obtain B cell and cell senescence related hub genes. Then the key genes for AD were screened by intersection, Mendelian randomization (MR), receiver operating characteristic (ROC) curve, and Wilcoxon test. Additionally, enrichment analysis, immune infiltration analysis, and molecular docking were performed to investigate the molecular mechanism of key genes and drug targets related to key genes, respectively. Results In this study, CCDC86 and PARP9 were identified as key genes, genetic association analysis suggested CCDC86 correlates with higher AD susceptibility while PARP9 tends to correlate with lowered AD risk. We also found that these two key genes were highly correlated with B cells, and the abundance of B cells in AD increased significantly. Finally, our calculation revealed that the binding free energy between PARP9 and bisphenol A was −7.6 kcal/mol, implying a favorable simulated binding tendency between the two molecules. Conclusions These findings suggest that PARP9 may serve as a promising and reliable drug target for clinical therapy, which may represent a tentative candidate worthy of further experimental validation for subsequent biomarker and therapeutic target research in AD.