4,4'-methylenediphenol reduces Aβ-induced toxicity in a model of Alzheimer's disease.

Introduction: is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of , and, in recent years, this herb has also been used in the treatment of Alzheimer's disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4'-methylenediphenol, a key active ingredient of , can mitigate amyloid-β (Aβ)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD.

Methods: We investigated the effects of 4,4'-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4'-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action.

Results: 4,4'-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4'-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased Aβ protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4'-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4'-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in Aβ toxicity; importantly, our results suggested that these effects of 4,4'-methylenediphenol were mediated, at least partly, via the activation of DAF-16.

Conclusion: We have demonstrated that 4,4'-methylenediphenol can reduce Aβ-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of and its active ingredients.