Transcriptomic and experimental validation identifies SOX6 and LDLRAD3 as key factors in vascular dementia

Abstract Vascular dementia (VaD) is a leading cause of cognitive decline, yet its underlying molecular mechanisms remain incompletely understood. This study aims to investigate the alterations associated with VaD in neuronal and endothelial cells by integrating single-nucleus RNA sequencing (snRNA-seq) with microarray data from postmortem VaD brain tissues. Using high-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning approaches, we identified SOX6 in neurons and LDLRAD3 in endothelial cells as key factors associated with VaD pathology. Functional enrichment analyses revealed that glutamatergic synapses and MAPK signaling are critical pathways in neurons, while the MAPK signaling pathway, lipid metabolism, and atherosclerosis in endothelial cells contribute to VaD progression. In a mouse model of post-stroke cognitive impairment induced by transient middle cerebral artery occlusion (tMCAO), SOX6 and LDLRAD3 were significantly upregulated at both the mRNA and protein levels, supporting their roles in VaD. These findings provide novel insights into potential therapeutic targets for VaD and highlight the importance of endothelial and neuronal interactions in disease progression.