Exploring the Remodeling of the Microglial Communication Network and the Role of CADM1 in Vascular Dementia (VaD) Based on Single-Nucleus Transcriptomics

INTRODUCTION: Vascular dementia (VaD) is characterized by neurovascular unit dysfunction and neuroinflammation. However, the molecular regulators linking microglial activation to remodeling of intercellular communication remain incompletely understood. METHODS: The human postmortem single-nucleus RNA-sequencing dataset GSE282111 was analyzed using Seurat-based dimensionality reduction and clustering, differential-expression analysis, CellChat, and functional enrichment. Candidate genes associated with microglial polarization were screened. An oxygen-glucose deprivation (OGD) model in murine BV2 microglial cells combined with CADM1 knockdown was used for in vitro validation of microglial marker expression and TNF-pathway components. RESULTS: Six major brain cell populations were identified, and cell-type proportions differed between control and VaD samples. CADM1, CYTIP, and MSR1 were identified as candidate genes associated with microglial polarization and were upregulated in VaD. CellChat analysis indicated remodeling of microglia-centered communication, including altered SPP1 and TGFβ signaling. In the OGD model, CADM1 silencing reduced CD16 expression and TNF-pathway components while increasing CD206 expression, indicating that CADM1 modulates microglial activation-related marker patterns and inflammatory signaling under ischemic stress. CONCLUSION: CADM1 emerges as a candidate regulator associated with microglial activation and TNF signaling in VaD. These exploratory findings support further investigation of the CADM1-TNF axis; however, independent clinical cohorts, chronic in vivo VaD models, and additional gain-of-function or rescue studies are required before diagnostic or therapeutic relevance can be established.