Cerebroprotein hydrolysate-I ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via the p53/SAT1/ALOX15 signalling pathway

Ferroptosis, an iron-dependent lipid peroxidation-driven cell death pathway, has been linked to the development of Alzheimer's disease (AD). However, the role of ferroptosis in the pathogenesis of AD remains unclear. Cerebroprotein hydrolysate-I (CH-I) is a mixture of peptides with neurotrophic effects that improves cognitive deficits and reduces amyloid burden. The present study investigated the ferroptosis-induced signalling pathways and the neuroprotective effects of CH-I in the brains of AD transgenic mice. Seven-month-old male APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with intraperitoneal injections of CH-I and saline for 28 days. The Morris water maze test was used to assess cognitive function. CH-I significantly improved cognitive deficits and attenuated beta-amyloid (Aβ) aggregation and tau phosphorylation in the hippocampus of APP/PS1 mice. RNA sequencing revealed that multiple genes and pathways, including ferroptosis-related pathways, were involved in the neuroprotective effects of CH-I. The increased levels of lipid peroxidation, ferrous ions, reactive oxygen species (ROS), and altered expression of ferroptosis-related genes (recombinant solute carrier family 7, member 11 (SLC7A11), spermidine/spermine N1-acetyltransferase 1 (SAT1) and glutathione peroxidase 4 (GPX4)) were significantly alleviated after CH-I treatment. Quantitative real-time PCR and western blotting were performed to investigate the expression of key ferroptosis-related genes and the p53/SAT1/arachidonic acid 15-lipoxygenase (ALOX15) signalling pathway. The p53/SAT1/ALOX15 signalling pathway was found to be involved in mediating ferroptosis, and the activation of this pathway was significantly suppressed in AD by CH-I. CH-I demonstrated neuroprotective effects against AD by attenuating ferroptosis and the p53/SAT1/ALOX15 signalling pathway, thus providing new targets for AD treatment.