Broussonetia papyrifera fruit extract attenuates Alzheimer's pathogenesis via disrupting the vicious cycle of Aβ and oxidative stress in C. elegans and cellular models.

ETHNOPHARMACOLOGICAL RELEVANCE: The dried fruit of Broussonetia papyrifera (L.) Vent., known as Fructus Broussonetiae (FB) in Traditional Chinese Medicine, is a kidney-nourishing herb historically prescribed to combat fatigue and age-related cognitive decline. This traditional application suggests potential efficacy against multifactorial neurodegenerative disorders like Alzheimer's disease (AD) AIM OF THE STUDY: This study aimed to investigate whether the ethyl acetate fraction of FB (FBA) could attenuate AD pathogenesis by disrupting the reciprocal exacerbation between Aβ proteotoxicity and oxidative stress.

MATERIALS AND

METHODS

The neuroprotective effects and mechanisms of FBA were evaluated in Caenorhabditis elegans models expressing human Aβ and in mammalian cellular models. Assessments included behavioral assays, histological staining, measurements of mitochondrial function, oxidative stress markers, and transcriptomic analyses. Key bioactive constituents were traced through bioactivity-guided fractionation.

RESULTS

FBA significantly alleviated Aβ-induced paralysis, improved locomotor performance, and reduced Aβ oligomerization and deposition in C. elegans. Concurrently, FBA restored mitochondrial function by enhancing membrane potential and abundance, and mitigated oxidative damage. In cellular models, FBA inhibited Aβ secretion, attenuated glutamate-induced excitotoxicity, and improved ATP production. At the molecular level, these benefits were linked to enhanced cellular defense mechanisms, including activation of the NRF2-mediated antioxidant pathway (elevated HO-1 and NQO1) and regulation of apoptotic signaling via reduced TP53 activity and an increased BCL-2/BAX ratio.

CONCLUSIONS

This study elucidates the modern pharmacological basis by which the active fraction of Broussonetia papyrifera fruit (FBA) disrupts the vicious cycle of Aβ-oxidative stress through multiple mechanisms, thereby improving Alzheimer's disease pathology. It provides a scientific explanation for its traditional anti-aging effects.