Aberrant signals in vascular dementia: Pleiotrophin/laminin pathway and glutamate metabolic dysregulation

Vascular dementia (VaD), the second most common cause of dementia, is closely associated with chronic cerebral hypoperfusion and progressive cognitive decline; however, its molecular and cellular basis remains incompletely understood. Dysregulated intercellular communication within the neurovascular unit may contribute to the cellular and pathological alterations observed in VaD. To identify candidate signaling pathways associated with VaD, we integrated single-cell transcriptomic analysis, microarray data analysis, pseudotemporal trajectory analysis, and experimental validation. Pleiotrophin (PTN) and LAMININ signaling emerged as consistently altered intercellular communication pathways and were associated with microglial state transitions along pseudotime. In a right unilateral common carotid artery occlusion (rUCCAO) mouse model, VaD mice exhibited cognitive impairment, microglial activation, myelin loss, white matter injury, enhanced inflammatory responses, and oxidative stress. Expression analyses further confirmed alterations in PTN- and laminin-related molecules, whereas untargeted metabolomics revealed concurrent disturbances in glutamate-related metabolism. These molecular and metabolic alterations were associated with behavioral deficits and VaD-related pathological changes. Collectively, our findings identify altered PTN/laminin signaling and glutamate metabolic dysregulation as candidate molecular features of VaD and provide a basis for investigating their functional relevance. Pathway-specific functional studies are still required to establish their causal contributions to VaD progression.