Chaetoglobosin F Attenuates Amyloid-β-Induced Neurotoxicity in Caenorhabditis elegans by Regulating Autophagy and Oxidative Stress Via the Insulin/IGF-1 and p38 MAPK Pathways.

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which no effective clinical therapies currently exist. The neuroprotective potential of Chaetoglobosin F (CF), a fungal secondary metabolite, was investigated in this study using a Caenorhabditis elegans (C. elegans) model of AD that are transgenic nematodes expressing amyloid-beta (Aβ). Key parameters evaluated included paralysis rate, lifespan, motor and cognitive functions, Aβ plaque aggregation, intracellular reactive oxygen species (ROS), and autophagosome formation. The transcriptional levels of genes were examined by real time PCR. Results showed that treatment with CF significantly delayed paralysis, extended lifespan, and ameliorated Aβ-induced deficits in locomotion and chemotaxis. CF markedly reduced Aβ plaque accumulation, suppressed intracellular ROS levels, and promoted autophagosome formation. Furthermore, CF had potent inhibitory effects on acetylcholinesterase (AChE) activity. These beneficial effects were correlated with the upregulation of crucial genes, including daf-16, skn-1, pmk-1, mtl-1, unc-51, bec-1, lgg-1, sod-1 and sod-3, which confirmed the improving antioxidant defenses and autophagy. Our findings demonstrate that CF confers strong neuroprotection against Aβ-induced toxicity in C. elegans by co-regulating oxidative stress and autophagy through the Insulin/IGF-1 (IIS) and p38 MAPK signaling pathways. These results suggest that CF is a promising natural compound for further investigation as a potential therapeutic agent for AD.