Abstract
Vascular dementia (VaD), the second-leading cause of dementia, is primarily a white matter ischemic disease with no direct therapies. Cell-cell interactions within lesion sites dictate disease progression or repair. To elucidate key intercellular pathways, we employ a VaD mouse model with focal ischemia replicating many elements of the complex pathophysiology of human VaD combined with transcriptomic and functional analyses. By integrating cell-type-specific mouse VaD transcriptomes and human VaD single-nucleus RNA sequencing (snRNA-seq) data plus a custom ligand-receptor database (4,053 human and 2,032 mouse pairs), conserved dysregulated intercellular pathways in both species are identified. We demonstrate that two intercellular signaling systems, Serpine2-Lrp1 and CD39-A3AR, are disrupted in VaD. Reduced Serpine2 expression enhances oligodendrocyte progenitor cell (OPC) differentiation, promoting repair, while an A3AR-specific agonist-currently in clinical trials for psoriasis-restores tissue integrity and behavioral function in the VaD model. This study reveals intercellular signaling targets and provides a foundation for developing innovative therapies for VaD.