Oleracein E Rejuvenates Senescent Hippocampal NSCs by Inhibiting the ERK1/2‐mTOR Axis to Improve Cognitive Dysfunction in Vascular Dementia

Vascular dementia (VD) is one of the most prevalent forms of dementia, yet effective treatments remain limited. Our previous research identified hippocampal neural stem cells (hNSCs) senescence as a key contributor to VD progression and suggested that reducing hNSC senescence could help reverse cognitive impairment. In this study, we investigated whether Oleracein E (OE), a phenolic antioxidant alkaloid, could alleviate hNSC senescence and improve cognitive function in VD. Using a two-vessel occlusion mouse model of VD, we found that OE treatment significantly reduced hNSCs senescence, restored proliferation and neuronal differentiation capacities, and improved cognitive performance. Mechanistically, OE exerted its effects by inhibiting ERK1/2 phosphorylation and suppressing mTOR activation. Furthermore, pharmacological activation of mTOR with MHY1485 partially abolished the antisenescence effects of OE in hNSCs. These findings suggest that OE may counteract senescence-related neurogenesis dysfunction and cognitive decline in VD, highlighting its potential as a therapeutic intervention.