Intercellular Signaling Pathways as Therapeutic Targets for Vascular Dementia Repair
Tian, M.; Kawaguchi, R.; Shen, Y.; Machnicki, M.; Villegas, N. G.; Cooper, D. R.; Montgomery, N.; Haring, J.; Lan, R.; Yuan, A. H.; Williams, C. K.; Magaki, S.; Vinters, H. V.; Zhang, Y.; De Biase, L. M.; Silva, A. J.; Carmichael, S. T.
Show abstract
Vascular dementia (VaD) is a white matter ischemic disease and the second-leading cause of dementia, with no direct therapy. Within the lesion site, cell-cell interactions dictate the trajectory towards disease progression or repair. To elucidate the underlying intercellular signaling pathways, a VaD mouse model was developed for transcriptomic and functional studies. The mouse VaD transcriptome was integrated with a human VaD snRNA-Seq dataset. A custom-made database encompassing 4053 human and 2032 mouse ligand-receptor (L-R) interactions identified significantly altered pathways shared between human and mouse VaD. Two intercellular L-R systems, Serpine2-Lrp1 and CD39-A3AR, were selected for mechanistic study as both the ligand and receptor were dysregulated in VaD. Decreased Seprine2 expression enhances OPC differentiation in VaD repair. A clinically relevant drug that reverses the loss of CD39-A3AR function promotes tissue and behavioral recovery in the VaD model. This study presents novel intercellular signaling targets and may open new avenues for VaD therapies.
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