2. Academic Validation
  3. Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications

Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications

  • Cell. 2025 Jun 24:S0092-8674(25)00636-1. doi: 10.1016/j.cell.2025.06.002.
Min Tian 1,  Riki Kawaguchi 2,  Yang Shen 3,  Michal Machnicki 1,  Nikole G Villegas 1,  Delaney R Cooper 1,  Natalia Montgomery 1,  Ying Cai 3,  Jacqueline Haring 1,  Ruirui Lan 1,  Angelina H Yuan 1,  Christopher K Williams 4,  Shino Magaki 4,  Harry V Vinters 4,  Ye Zhang 2,  Lindsay M De Biase 5,  Alcino J Silva 3,  S Thomas Carmichael 6
Affiliations

Affiliations

  • 1 Department of Neurology, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 2 Department of Psychiatry and Biobehavioral Sciences, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 3 Neurobiology, Psychiatry, and Psychology Departments and Integrative Center for Learning and Memory, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 4 Department of Neurology, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 5 Department of Physiology, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • 6 Department of Neurology, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: scarmichael@mednet.ucla.edu.
PMID: 40592323 DOI: 10.1016/j.cell.2025.06.002
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.

Keywords

A3AR; CD39; L-R pairs; Serpine2; VaD; WM; adenosine receptor 3; cell-cell interaction; glia; learning and memory; ligand-receptor pairs; motor deficit; stroke; tissue repair; vascular dementia; white matter.

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