Vitamin E and melatonin synergistically attenuate sleep deprivation-induced Nrf2 dysregulation and hippocampal ferroptosis in Alzheimer's disease mouse models.

Abstract

BACKGROUND: Emerging evidence highlights a bidirectional link between Alzheimer's disease (AD) and sleep disturbances. This study investigates whether early chronic sleep deprivation (CSD) exacerbates AD progression by impairing the antioxidant transcription factor Nrf2 and promoting hippocampal ferroptosis. METHODS: 5xFAD transgenic mice underwent early CSD. Behavioral tests (Morris water maze, novel object recognition, open field) assessed cognition and anxiety. Histological and molecular analyses evaluated neuronal loss, phosphorylated tau (p-tau), oxidative stress markers (Fe2+, ROS, MDA, GSH), and expression/localization of Nrf2, Keap1, and ferroptosis-related proteins (GPX4, HO-1, ACSL4, SLC7A11). Interventions included Nrf2 knockout, AAV-mediated Nrf2 overexpression, melatonin, vitamin E (Vit.E), their combination, and the ferroptosis inhibitor liproxstatin1(Lip-1). Data were analyzed with t-tests and ANOVA (p < 0.05). RESULTS: Early CSD accelerated cognitive decline, hippocampal neuronal loss, and p-tau pathology in 5xFAD mice. CSD triggered Nrf2 depletion, suppressed its nuclear translocation, and downregulated GPX4 and HO-1, leading to oxidative stress and ferroptosis. Nrf2 knockout worsened these deficits. While melatonin or Lip-1 attenuated damage, combined melatonin and Vit.E most effectively reactivated Nrf2, inhibited ferroptosis, reduced p-tau, and restored cognitive function. CONCLUSIONS: Early CSD promotes AD pathogenesis via Nrf2 dysfunction, driving oxidative stress and ferroptosis in the hippocampus. Preemptive intervention targeting sleep and Nrf2 activation-particularly through combined melatonin and vitamin E-represents a promising strategy to delay neurodegeneration in at-risk individuals.

Key Findings

• Early chronic sleep deprivation (CSD) accelerates cognitive decline, hippocampal neuronal loss, and phosphorylated tau pathology in Alzheimer's disease mouse models.
• CSD induces Nrf2 depletion and suppresses its nuclear translocation, leading to oxidative stress and hippocampal ferroptosis.
• Combined treatment with melatonin and vitamin E synergistically reactivates Nrf2, inhibits ferroptosis, reduces tau pathology, and restores cognitive function more effectively than either treatment alone.

Clinical Significance

Citation

Gao Qun, Sun Jun, Hei Boet al.. Vitamin E and melatonin synergistically attenuate sleep deprivation-induced Nrf2 dysregulation and hippocampal ferroptosis in Alzheimer's disease mouse models. Experimental neurology. 2026-Apr-24.