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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 et al.. Cell, 2025-07-02
Topic: Brain proteins, microglia and lab models
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.
Key findings
- 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.
Why it matters
In a mouse model of vascular dementia, two intercellular signaling systems were disrupted, and an A3AR-specific agonist restored tissue integrity and behavioral function. This study reveals intercellular signaling targets and provides a foundation for developing therapies for vascular dementia, though findings are from animal models.
Study details
- Evidence strengthLow
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cell) |
| Journal's citation record | 4 / 4 | Cell: journal h-index 1,220 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 21 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 6.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 21 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Stanley Thomas Carmichael: h-index 83 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, Los Angeles: institution h-index 1,923 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40592323) |
| Free to read | 2 / 2 | Free to read |
| Total | 45 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Tian, M., Kawaguchi, R., Shen, Y., Machnicki, M., Villegas, N. G., Cooper, D. R., et al. (2025). Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications. Cell. https://doi.org/10.1016/j.cell.2025.06.002
Vancouver
Tian M, Kawaguchi R, Shen Y, Machnicki M, Villegas NG, Cooper DR, et al. Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications. Cell. 2025. doi:10.1016/j.cell.2025.06.002. PMID: 40592323.
BibTeX
@article{tian2025-40592323,
author = {Tian, Min and Kawaguchi, Riki and Shen, Yang and Machnicki, Michał and Villegas, Nikole G. and Cooper, Delaney R. and Montgomery, Natalia and Cai, Ying and others},
title = {{Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications}},
journal = {Cell},
year = {2025},
doi = {10.1016/j.cell.2025.06.002},
pmid = {40592323},
url = {https://doi.org/10.1016/j.cell.2025.06.002}
}
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