UCLA researchers from the Department of Neurology have discovered and validated intercellular signaling pathways that can be therapeutically targeted to drive repair and functional recovery in vascular dementia.
BACKGROUND: Vascular dementia (VaD) is the second leading cause of dementia and is driven by ischemic injury to cerebral white matter, producing progressive cognitive and motor decline. Existing animal models suffer from several limitations, such as a reliance on global hypoperfusion, and incompletely recapitulate human VaD pathophysiology. There are no medical therapies that directly treat vascular dementia. Cells of the cerebral white matter reside in a neurovascular niche where ligand receptor signaling dictates injury responses. A systematic map of these intercellular pathways in VaD has been lacking, limiting rational target selection for disease-modifying therapy. Thus, there is a critical need to decipher these pathways to further treatment and therapeutic development for VaD.
INNOVATION: UCLA researchers led by Dr. S. Thomas Carmichael have discovered intercellular (cell-to-cell) signaling pathways that can serve as therapeutic targets in vascular dementia. UCLA researchers developed a new mouse model of vascular dementia that closely mimics the human disease. Using cell type-specific RNA sequencing, they used this model to uncover how different brain cells communicate with each other during injury and repair. They then compared this animal model data set in vascular dementia with human cell-type specific RNA sequencing from patients with vascular dementia. By mapping thousands of communication signals between cells in the brain in vascular dementia, the team identified two key pathways that can be targeted for therapy. They further showed that inhibiting the first pathway helped oligodendrocyte progenitor cells mature and restore myelin, improving memory in mice. The second identified pathway was shown to be down-regulated in vascular dementia. Remarkably, a drug already in late-stage clinical trials for psoriasis was able to boost this pathway in mice even when given weeks after injury. Treatment led to smaller brain lesions, more myelin, and recovery of both memory and motor function. Together, this research highlights promising new strategies for repairing brain damage in vascular dementia and shows that some therapies could be rapidly moved into the clinic.
POTENTIAL APPLICATIONS:
- Disease-modifying therapeutics for vascular dementia (targeting multiple pathways)
- Therapeutics for other white-matter ischemic conditions
- Using cell type ligand-receptor signatures to monitor patient response/stratify patients with vascular dementia
ADVANTAGES:
- Translatable, repair-focused strategy (activating endogenous repair mechanisms)
- Unmet clinical need—no current therapy for vascular dementia
- Targets are conserved across human and mouse datasets
- Drugs that target one of the identified pathways are already in late-stage clinical trials
- Mouse model is more closely mirrors human disease pathophysiology
DEVELOPMENT-TO-DATE: UCLA researchers have developed a mouse model of vascular dementia (VaD) and used this in vivo model to construct a comprehensive white matter cell type VaD interactome from TRAP/FACS RNA sequencing data. Modulation of identified pathways in vivo promoted tissue repair and behavioral recovery in the VaD model.
Related Papers (from the inventors only):
- Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications Tian M, Kawaguchi R, Shen Y, Machnicki M, Villegas NG, Cooper DR, Montgomery N, Cai Y, Haring J, Lan R, Yuan AH, Williams CK, Magaki S, Vinters HV, Zhang Y, De Biase LM, Silva AJ, Carmichael ST.. Cell. 188:5157-5174.e20. doi: 10.1016/j.cell.2025.06.002.
- Mitroi DN, Tian M, Kawaguchi R, Lowry WE, Carmichael ST. Single-nucleus transcriptome analysis reveals disease- and regeneration-associated endothelial cells in white matter vascular dementia. J Cell Mol Med. 2022 26:3183-3195. doi: 10.1111/jcmm.17315.
Keywords: RNA-sequencing; cell-type specificity; FACS; TRAP; transcriptomics; cell signaling; Vascular dementia (VaD); white matter (WM); glia; cell-cell interaction; ligand-receptor (L-R) pairs; learning and memory; motor deficit; tissue repair; extracellular matrix (ECM); G protein-coupled receptors (GPCR); Serpine2; Lrp1; CD39; adenosine receptor 3 (A3AR).