Researchers here report an advance in understanding the biochemistry of pathological interactions between cell types in the context of vascular dementia. After mapping gene expression levels in healthy and diseased vascular tissue, the researchers find a possible basis for therapy in one specific set of altered expression levels observed in microglia and oligodendrocyte. They present initial evidence for restored expression of two genes to reduce vascular dysfunction and pathology. This sort of approach is inherently compensatory, to eliminate a maladaptive reaction without addressing underlying causes. Is likely to be more limited in benefits than addressing those causes, because the causes will continue to produce other harms. Nonetheless, this is the way that the research community usually proceeds.
Vascular dementia (VaD) accounts for approximately 25% of all dementia cases. Currently, there are no direct treatments for VaD, and existing symptomatic therapies, such as cholinesterase inhibitors and memantine, demonstrate limited efficacy and fail to target the underlying vascular pathology. VaD arises from impaired cerebral blood flow due to cerebrovascular pathologies, including ischemic stroke, microinfarcts, or chronic small vessel disease.
A major barrier to advancing VaD research is the incomplete understanding of cell-type-specific responses within the neurovascular unit (NVU) - a dynamic interplay of multiple cell types. This NVU maintains cellular homeostasis and orchestrates responses to injury through intricate cell-cell interactions mediated by ligand-receptor (L-R) signaling. In VaD, ischemic injury originates in endothelial cells and propagates through the neurovascular niche, disrupting intercellular communication and leading to tissue damage and cognitive decline. The intercellular networks or "interactome" specific to VaD remains largely unexplored.
To address these challenges, we performed cell-type-specific RNA-seq to profile transcriptional changes in glial and vascular cells. Notably, WM glial and vascular cells exhibit specific transcriptional profiles compared with cortical and whole-brain datasets. The ischemic lesions also perturb WM-associated aging genes. We constructed a comprehensive VaD interactome, identifying conserved signaling pathways altered in both human and mouse, and prioritized two candidate L-R systems for functional validation: (1) the extracellular matrix component Serpine2 and its receptor Lrp1, which regulate oligodendrocyte differentiation and myelination, and (2) the CD39-A3AR signaling axis, which modulates microglial activation and tissue repair. 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.
Link: https://doi.org/10.1...ell.2025.06.002
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