Growing evidence suggests that plant compounds are emerging as a tremendous source for slowing the onset and progression of Alzheimer's disease (AD). Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid with some hypoglycemic, anticancer, and antiinflammatory activities. However, the pharmacological effects of UNA on AD are still unknown. In the present experiments, the effects and mechanisms of UNA on AD were firstly explored by H2O2-induced PC12 cells and Aβ1-42-induced AD model of Caenorhabditis elegans (C. elegans). The results showed that UNA increased the cell viability and the level of mitochondrial membrane potential and reversed apoptosis in H2O2-induced PC12 cells, and Nrf2 and HO-1 were involved in this process. UNA also decreased the phosphorylation of related proteins in the MAPK signaling pathway. Meanwhile, we found that UNA upregulated cellular catalase levels and decreased ROS production. Besides, UNA could activate the Nrf2 /HO-1 signaling pathway and upregulate its protein expression under oxidative stress conditions, whereas Nrf2 and HO-1 inhibitors partially eliminated the protective ability of UNA. The results of in vivo experiments showed that UNA prolonged the lifespan and enhanced the health parameters of AD C. elegans and reduced Aβ1-42-induced neurotoxicity and ROS levels. Moreover, UNA increased GFP-tagged LGG-1 puncta in DA2123 C. elegans. Further mechanistic studies suggested that the protection of UNA on AD C. elegans may be through modulation of the MAPKs/Nrf2/HO-1 pathway. These results highlight the neuroprotective potential of UNA and suggest that UNA may be an effective therapeutic agent for alleviating AD.
Keywords: Alzheimer’s disease; Antioxidant; Apoptosis; MAPKs/Nrf2/HO-1 signaling pathway; Ursonic acid.
© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.