Identification of an S-nitrosylation-Related Gene Signature for Alzheimer’s Disease via Bulk and Single-Cell Transcriptomic Profiling
Junfei Yi, Jiang Tan, Lin Zhou, Qiang Gong, Jiliang HuIntroduction:
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with limited early-stage diagnostic tools and disease-modifying therapies. While Post-Translational Modifications (PTMs) are known to regulate AD pathogenesis, the comprehensive landscape of Snitrosylation and its role in driving cerebrovascular and metabolic dysfunction remains poorly understood.
Methods:
Three independent bulk transcriptomic datasets (GSE138260, GSE29378, GSE5281) and single-cell RNA sequencing (scRNA-seq) profiles (GSE157827) were integrated to systematically evaluate PTM enrichment patterns using single-sample Gene Set Enrichment Analysis (ssGSEA). A Protein-Protein Interaction (PPI) network was constructed to identify hub genes, which were further validated for cell-type specificity and functional pathways.
results:
Among 15 evaluated PTMs, S-nitrosylation exhibited the highest enrichment score in AD tissues. We identified a five-gene hub signature—HSP90AB1, ITGA6, KLF4, SOX2, and VIM—that significantly correlates with S-nitrosylation activity. Specifically, SOX2, VIM, KLF4, and ITGA6 were significantly upregulated in AD, while HSP90AB1 was downregulated. Notably, scRNA-seq analysis revealed that VIM and ITGA6 are specifically upregulated in brain endothelial cells, aligning with the enrichment of focal adhesion and cell adhesion pathways. Conversely, the downregulation of HSP90AB1 was linked to impaired oxidative phosphorylation and proteostasis.
Results:
Among the evaluated PTM-related gene sets, the S-nitrosylation-related signature showed significant enrichment in AD tissues. A five-gene hub signature—HSP90AB1, ITGA6, KLF4, SOX2, and VIM—that significantly correlates with S-nitrosylation activity was identified. Specifically, SOX2, VIM, KLF4, and ITGA6 were significantly upregulated in AD, while HSP90AB1 was downregulated. Notably, scRNA-seq analysis revealed that VIM and ITGA6 are specifically upregulated in brain endothelial cells, aligning with the enrichment of focal adhesion and cell adhesion pathways. Conversely, downregulation of HSP90AB1 was associated with impaired oxidative phosphorylation and proteostasis.
Discussion:
This study identifies S-nitrosylation-related transcriptional signatures associated with AD and highlights potential roles of VIM, ITGA6, and HSP90AB1 in endothelial dysfunction and metabolic regulation, providing new insights into the molecular mechanisms underlying AD pathogenesis.
Conclusion:
A five-gene S-nitrosylation signature (HSP90AB1, ITGA6, KLF4, SOX2, VIM) associated with AD was identified; the endothelial enrichment of VIM and ITGA6 and the loss of HSP90AB1 nominate these three genes as priority candidates for experimental validation and, potentially, therapeutic targeting.