Targeting CD38 to alleviate brain endothelial cell dysfunction and cognitive impairment in vascular dementia

Vascular dementia (VaD) is a leading cause of cognitive decline, closely associated with cerebrovascular endothelial cell (CEC) dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation. CD38, an enzyme implicated in neuroinflammation and cellular senescence, has emerged as a potential regulator of these pathological processes, yet its role in CEC dysfunction within the context of VaD remains unclear. In this study, we investigated the impact of CD38 on CEC dysfunction using a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Our results demonstrate that BCAS significantly reduces cerebral blood flow (CBF), increases BBB permeability, and induces cognitive deficits, all accompanied by elevated CD38 expression in CECs and heightened levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Notably, treatment with the selective CD38 inhibitor 78c (10 mg/kg, twice daily for 1 month) effectively mitigated these effects, reducing white matter damage, improving CBF, enhancing the expression of CEC tight junction proteins, and decreasing neuroinflammation and BBB disruption. In vitro experiments further revealed that 78c attenuates TNF-α-induced CD38 expression and inflammatory responses in CECs, likely through the NOX4/eNOS aixs. These findings identify CD38 as a crucial mediator of CEC dysfunction in VaD, linking chronic cerebral hypoperfusion to neurovascular damage.