Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications
Min Tian, Riki Kawaguchi, Yang Shen, Michał Machnicki, Nikole G. Villegas, Delaney R. Cooper, Natalia Montgomery, Ying Cai, Jacqueline Haring, Ruirui Lan, Angelina H. Yuan, Christopher Kwesi O. Williams, Shino Magaki, Harry V. Vinters, Ye Zhang, Lindsay M. De Biase, Alcino J. Silva, S. Thomas Carmichael
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.