JMJD6 Inhibits the Ferroptosis of Neurons in Alzheimer's Disease through Driving H4R3 Symmetrical Dimethylation of GPX4

Histone methylation is a key hallmark of Alzheimer's disease (AD). JMJD6 functions in a neuro-protective role. The purpose of this study is to explore the role of JMJD6 in AD. Neurons are exposed to Aβ₁₋₄₂ to establish in vitro AD model. Neurons are treated with RSL3 to induce neuronal ferroptosis. mRNA expression is detected using qRT-PCR. Protein expression is determined using Western blot. The levels of ROS, GSH, MDA, ferrous iron, and C11-BODIPY are analyzed. Neuronal death is detected using PI staining. H4R3 symmetrical dimethylation of GPX4 is analyzed using ChIP and luciferase assays. We found that Aβ₁₋₄₂ exposure promotes iron overload and lipid peroxidation, driving neuronal ferroptosis. Aβ₁₋₄₂ exposure inhibits the expression of JMJD6. However, overexpression of JMJD6 reverses Aβ₁₋₄₂ exposure-induced neuronal ferroptosis. Moreover, JMJD6 promotes H4R3 symmetrical dimethylation and upregulation of GPX4, driving the release of anti-oxidant GSH. Furthermore, JMJD6 overexpression alleviated cognitive impairment and neuronal ferroptosis in AD mouse models. However, downregulation of GPX4 mediates neuronal ferroptosis. In conclusion, JMJD6 protects against neuronal ferroptosis in AD via upregulating GPX4.