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Alzheimer’s disease (AD) is a common age-related chronic and neurodegenerative disease that has become a global health problem. AD pathogenesis is complex, and the clinical efficacy of commonly used anti-AD drugs is suboptimal. Recent research has revealed a close association between AD-induced damage and the activation of ferroptosis signaling pathways. Chrysophanol (CHR) the principal medicinal component of Rhubarb, has been reported to have anti-AD effects and can reduce ROS levels in AD-damaged models. AD has been linked to the activation of ferroptosis signaling pathways, which has an important feature of higher levels of reactive oxygen species (ROS). Therefore, the present study explored whether CHR had an anti-AD effect by regulating the ferroptosis levels in AD injury models. Morris water maze, novel object recognition test, Y-maze test, Hematoxylin–eosin (H&E) staining, western blotting, ROS measurement, GPx activity measurement, LPO measurement, transmission electron microscopy, live/dead cell staining were used to investigate the changes in spatial memory level and ferroptosis level in AD model, and the intervention effect of CHR. CHR improved the spatial memory level of AD rat models, reduced the level of hippocampal neuron damage, and improved the survival rate of PC12 cells damaged by β-amyloid (Aβ). Meanwhile, CHR increased glutathione peroxidase-4 (GPX4) protein expression, GPx activity, and GSH, decreased ROS and LPO levels in AD rat models and Aβ-damaged PC12 cells, and improved mitochondrial pathological damage. Our findings suggest that CHR may play a protective role in AD injury by lowering ferroptosis levels, which may provide a potential pathway for developing drugs for AD. However, the mechanism of CHR’s role requires further investigation.

This study was aimed to investigate the effect of Chrysophanol (CHR) on Alzheimer’s disease. We also attempted to understand the potential mechanisms. An Alzheimer’s disease rat model was established using an intraperitoneal injection of d-galactose combined with an intracerebral injection of amyloid-β peptide (25–35), and the effect of CHR on the learning and memory ability, the hippocampal neurons change, the ultrastructure of the hippocampal CA1 region, the protein levels of CaM, CaMKK, CaMKIV, p-CaMKIV and p-tau in the hippocampus of rats were studied. The results showed that CHR significantly improved the cognitive deficits, alleviated hippocampal neurons damage, prevented the ultrastructure alteration of neurons in hippocampal CA1 region, and reduced the protein levels of CaM, CaMKK, p-CaMKIV and p-tau in the hippocampus of AD rats. These results suggested that Chrysophanol could improve memory ability of Alzheimer’s disease rat by inhibiting tau hyperphosphorylation and the CaM–CaMKIV signal pathway.