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
  • 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: [email protected].
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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