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Notch-1 suppressed vascular dementia via modulating AMPK/mTOR/TFEB/YAP signaling induced ferroptosis

Ling Zhu1, Zhihuan Wu2, Zhitao Zhang3

  • 1Department of Electromyography, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

European Journal of Medical Research
|January 20, 2026
PubMed
Abstract

Insights

Notch-1 protein prevents vascular dementia by inhibiting ferroptosis via the AMPK/mTOR/TFEB/YAP pathway. This molecular mechanism improves spatial memory and reduces neuronal damage in affected rats.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Vascular dementia (VD) is a debilitating neurological disorder with limited treatment options.
  • Ferroptosis, a regulated form of cell death, plays a significant role in the pathogenesis of VD.
  • The AMPK/mTOR/TFEB/YAP signaling pathway is implicated in cellular stress responses and survival.

Purpose of the Study:

  • To elucidate the molecular mechanism by which Notch-1 exerts neuroprotective effects against VD.
  • To investigate the role of Notch-1 in regulating ferroptosis within the context of VD.
  • To determine the involvement of the AMPK/mTOR/TFEB/YAP pathway in Notch-1-mediated protection against VD.

Main Methods:

  • In vivo studies utilized Sprague-Dawley rats subjected to a vascular dementia model, assessing spatial learning and memory via the water maze test.
  • Hippocampal protein expression was analyzed using Western blotting, and neuronal integrity was evaluated through Nissl staining.
  • In vitro studies employed cultured hippocampal cells to assess ferroptosis, apoptosis, Fe2+ levels, and protein expression under various stimuli.

Main Results:

  • Notch-1 overexpression (Notch1-OE) in vivo improved spatial learning and memory, reduced neuronal damage, and increased Nissl bodies in VD rats.
  • Notch1-OE upregulated SLC7A11 and downregulated NCOA4 expression, key regulators of ferroptosis.
  • In vitro, Notch-1 inhibited ferroptosis and apoptosis by suppressing P-AMPK and nuclear TFEB while increasing p-mTOR and nuclear YAP.

Conclusions:

  • Notch-1 plays a crucial role in preventing vascular dementia.
  • Notch-1 inhibits ferroptosis by modulating the AMPK/mTOR/TFEB/YAP signaling pathway.
  • Targeting Notch-1 offers a potential therapeutic strategy for vascular dementia.
Keywords:
AMPK/mTOR/TFEB/YAPFerroptosisNotch-1Vascular dementia

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