An 8-week Aerobic Exercise Intervention Mitigates Iron Overload And Reduces Ferroptosis In Cerebral Cortex Resulting From Hemoglobin Degradation By Activating Lipid Antioxidant Pathway

PURPOSE: This study aims to investigate the impact of aerobic exercise on iron homeostasis and the lipid antioxidant pathway in the cortex of Alzheimer's disease (AD) model mice. METHODS: Twenty six-month-old C57BL/6 (C57) and APP/PS1 (APP) mice were equally divided into aerobic exercise groups (C57-E and APP-E) and sedentary groups (C57-S and APP-S) for an 8-week period. Morris water maze test (MWM), iron detection, Western Blot and ELISA were conducted to assess behavioral performance, iron levels, iron storage, heme-iron intake and lipid antioxidant-related proteins in each group. RESULTS: MWM revealed an decrease in the number of platform crossings and time spent in the quadrant containing the platform for APP/PS1 mice (P = 0.013), while these measures showed an increase following aerobic exercise (P = 0.016). In iron detection, there was an increase in cortical iron levels in the APP/PS1 cortex (P = 0.040). Hemoglobin uptake carrier proteins ABCG2 (P = 0.017) and FLVCR2 (P = 0.029), and heme metabolic enzyme HO1 (P < 0.001) increased in APP/PS1 cortex. Meanwhile, a decrease in the expression levels of FTH (P = 0.017) and FTL (P = 0.036) was found in APP/PS1 cortex, which associated with the increase of NACO4 (P = 0.010). However, aerobic exercise increased the expression of Xc- (P = 0.050) and GPx4 (P = 0.014), enhancing the reduction of lipid peroxides by GPx4 and GSH. CONCLUSIONS: The increase in heme input proteins and heme oxygenase leads to elevated levels of free iron in the brain. The decrease in ferritin content fails to meet the storage needs for excess free iron within the cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, leading to ferroptosis and resulting in cognitive impairment in AD model mice. However, eight weeks of aerobic exercise induce activation of the Xc-/GPx4 pathway, which can reverse the aforementioned processes, thereby inhibiting ferroptosis in APP/PS1 mice, positively to the improvement and inhibition of AD.The authors would like to acknowledge support from the National Natural Science Foundation of China (NSFC) and the Fundamental Research Funds for the China Institute of Sport Science (23-55).