Bamboo Leaf Flavonoids from Phyllostachys glauca McClure Suppress the Progression of Alzheimer’s Disease Induced by Circadian Rhythm Disruption Through Regulating Hif3α/Rab7/TNFα/IL1β Pathway

Circadian rhythm disruption is a modifiable risk factor for Alzheimer's disease (AD) progression, marked by neuroinflammation, oxidative stress, and amyloid-β (Aβ) accumulation. Hypoxia-inducible factor 3α (Hif3α) has emerged as a key regulator of inflammatory and oxidative pathways. To evaluate the impacts of circadian disruption on AD progression and investigate the therapeutic potential of bamboo leaf flavonoids (BLFs), C57BL/6N mice (normal mice) and APP/PS1 transgenic mice (AD mice) were exposed to circadian disruption via randomized light exposure and stress, as the in vivo model. Then, BLFs were administered to assess effects on neuroinflammation, oxidative stress, and organ damage. Next, Nissl body staining and Aβ protein immunohistochemistry were performed to evaluate the effects of BLFs on brain pathology. Through transcriptome sequencing, key factors and the related pathway were screened out. In vitro, molecular mechanisms were explored in PC12 cells treated with Aβ42 and <i>Hif3α</i> siRNA fragments. Results demonstrated that circadian disruption increased oxidative stress and early liver and kidney damage degrees, with greater severity in AD mice. BLFs partially reversed oxidative damage and reduced Aβ deposition. Transcriptome analysis revealed upregulation of <i>Hif3α</i> in circadian-disrupted mice, linked to inflammation and oxidative stress. In vitro, the knockdown of <i>Hif3α</i> reduced inflammation and normalized protein expression, which could be regulated by BLFs and suppressed AD progression. In conclusion, circadian disruption exacerbated AD progression via regulating Hif3α/Rab7/TNFα/IL1β pathway. BLFs offered neuroprotection roles by mitigating inflammation and oxidative damage, highlighting Hif3α as a promising target for AD therapy and biomarker development.