The KEAP1/PGAM5/AIFM1-Mediated oxeiptosis pathway in Alzheimer's disease

Background: Alzheimer's Disease (AD) is a neurodegenerative disease with mitochondrial dysfunction and oxidative stress. Oxeiptosis is a cell death pathway sensitive to Reactive Oxygen Species (ROS). This study investigates the role of oxeiptosis pathway and mitochondrial damage in AD.

Methods: An AD model was developed in C57BL/6 mice by injecting Aβ_1-42 oligomers into the brain. Cognitive function was tested using the Morris water maze. Exposure of HT22 mouse hippocampal neurons to H₂O₂ induces oxidative stress. Protein levels of KEAP1, PGAM5 and AIFM1 were analyzed by western blot, and mitochondrial damage was observed with electron microscopy. Cell survival rates were using the CCK8 assay and flow cytometry after knocking down KEAP1, PGAM5 and AIFM1.

Results: The protein concentrations of KEAP1, PGAM5 and AIFM1 were found to be elevated in the hippocampal tissues of AD mice compared to control group, accompanied by mitochondrial damage in the hippocampal neurons of the AD group. Similarly, in the HT22 oxidative stress model, there was an increase in the protein levels of KEAP1, PGAM5 and AIFM1, along with observed mitochondrial damage. Following individual and combined knockdown of KEAP1, PGAM5 and AIFM1, cell survival rates under oxidative stress conditions were higher compared to H₂O₂ group, with no significant difference in cell survival rates among the knockdown groups.

Conclusion: This research underscores the critical role of the KEAP1/PGAM5/AIFM1-mediated oxeiptosis pathway in neuronal cell death, offering insights into potential therapeutic targets for mitigating neurodegeneration in AD.

AIFM1; Alzheimer’s Disease; KEAP1; Oxeiptosis; Oxidative Stress; PGAM5.