Alzheimer's disease (AD) incidence is rising with no effective treatments. Eleutheroside B (EB) has neuroprotective potential, but its therapeutic effects and mechanisms in AD are unclear. This study investigated EB's effects on AD pathologies and elucidated its underlying mechanisms using a transgenic Caenorhabditis elegans (C. elegans) model. We found that EB could ameliorate cognitive impairment, locomotor dysfunction, and shortened lifespan induced by amyloid-β(Aβ) and Tau aggregation in C. elegans, and reduce the relative expression levels of Aβ, Tau, and phosphorylated Tau (p-Tau) proteins. EB improved the health status and anti-aging capacity of the worms, as evidenced by prolonged healthspan, elevated pharyngeal pumping rate and body bend frequency, and increased body length and width. Notably, EB exhibited no observable toxicity even at high-dose administration. Furthermore, EB activated key stress-responsive transcription factors skn-1, daf-16, and hsf-1; it also increased the expression levels of antioxidant enzymes superoxide dismutase-3(SOD-3) and glutathione S-transferase 4(GST-4), decreased reactive oxygen species (ROS) levels, and elevated the expression of heat shock proteins Hsp-4 and Hsp-6. EB also reduced the accumulation of p62/SQST-1 protein, promoted the colocalization of lgg-1:GFP with lysosomes, and increased the relative mRNA expression of autophagy-related genes aak-2, unc-51, bec-1, vps-34, and lgg-1. After targeted knockdown of these genes, the protective effects of EB against AD-related pathologies were abolished. Our findings demonstrate that EB exhibits anti-aging properties and potential for ameliorating AD, which is likely mediated via antioxidative activities and autophagy induction.
