Apolipoprotein E is required for brain iron homeostasis in mice
Juan Ma,
Qian Guo,
Meng-Qi Shen,
Wei Li,
Qi-Xin Zhong,
Zhong-Ming Qian
Affiliations
Juan Ma
Department of Neurology, Affiliated Hospital, and Institute of Translational and Precision Medicine, Nantong University, 19 Qi Xiu Road, Nantong, Jiangsu, 226001, China; Laboratory of Neuropharmacology of Pharmacy School, and National Clinical Research Center for Aging and Medicine of Huashan Hospital, Fudan University, Shanghai, 201203, China
Qian Guo
Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, 881 Yonghe Road, Nantong, Jiangsu, 226001, China; Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, 99 Shangda Road, Shanghai, 200444, China; Corresponding author. School of Medicine, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
Meng-Qi Shen
Department of Neurology, Affiliated Hospital, and Institute of Translational and Precision Medicine, Nantong University, 19 Qi Xiu Road, Nantong, Jiangsu, 226001, China
Wei Li
Department of Neurology, Affiliated Hospital, and Institute of Translational and Precision Medicine, Nantong University, 19 Qi Xiu Road, Nantong, Jiangsu, 226001, China
Qi-Xin Zhong
Department of Cardiovascular Medicine, Shenzhen Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518034, China
Zhong-Ming Qian
Department of Neurology, Affiliated Hospital, and Institute of Translational and Precision Medicine, Nantong University, 19 Qi Xiu Road, Nantong, Jiangsu, 226001, China; Corresponding author. Institute of Translational and Precision Medicine, Nantong University, 19 Qi Xiu Road, Nantong, 226001, China.
Background: Apolipoprotein E deficiency (ApoE−/−) increases progressively iron in the liver, spleen and aortic tissues with age in mice. However, it is unknown whether ApoE affects brain iron. Methods: We investigated iron contents, expression of transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1), iron regulatory proteins (IRPs), aconitase, hepcidin, Aβ42, MAP2, reactive oxygen species (ROS), cytokines and glutathione peroxidase 4 (Gpx4) in the brain of ApoE−/− mice. Results: We demonstrated that ApoE−/− induced a significant increase in iron, TfR1 and IRPs and a reduction in Fpn1, aconitase and hepcidin in the hippocampus and basal ganglia. We also showed that replenishment of ApoE absent partly reversed the iron-related phenotype in ApoE−/− mice at 24-months old. In addition, ApoE−/− induced a significant increase in Aβ42, MDA, 8-isoprostane, IL-1β, IL-6, and TNFα and a reduction in MAP2 and Gpx4 in hippocampus, basal ganglia and/or cortex of mice at 24-months old. Conclusions: Our findings implied that ApoE is required for brain iron homeostasis and ApoE−/−-induced increase in brain iron is due to the increased IRP/TfR1-mediated cell-iron uptake as well as the reduced IRP/Fpn1 associated cell-iron export and suggested that ApoE−/− induced neuronal injury resulted mainly from the increased iron and subsequently ROS, inflammation and ferroptosis.
