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Vascular dementia (VaD) is characterized by chronic cerebral hypoperfusion, leading to cognitive decline. Impaired hippocampal neurogenesis is a crucial pathological feature of VaD. Delta-like 1 homolog (Dlk1)-Notch signaling may contribute to neural stem cell regulation, but the involvement of Dlk1-Notch signaling in impaired hippocampal neurogenesis during hypoperfusion is unclear. Here, we investigated the role of Dlk1 and Notch signaling in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). We found that BCAS increased Dlk1 levels in hippocampal tissue and cerebrospinal fluid, accompanied by elevated Notch intracellular domain (NICD) expression and reduced doublecortin (Dcx)-positive hippocampal cells. These changes were associated with impaired novel object recognition. In Neuro2a cells, hypoxia-mimetic treatment elevated NICD and extracellular Dlk1 and reduced cell viability, while pharmacological inhibition of Notch signaling partially rescued cell loss and attenuated these changes. These findings suggest that Dlk1-associated Notch activation correlates with impaired hippocampal neurogenesis and memory dysfunction under chronic hypoperfusion. Our results highlight a potential link between altered niche signaling and cognitive decline in VaD, providing a basis for further mechanistic investigation.
Moriyama et al. (Thu,) studied this question.