Apolipoprotein E is required for brain iron homeostasis in mice

• Published in: Redox biology Vol. 64; p. 102779
• Main Authors: Ma, Juan, Guo, Qian, Shen, Meng-Qi, Li, Wei, Zhong, Qi-Xin, Qian, Zhong-Ming
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2023; Elsevier
• Subjects: AD and amyloid beta; Animals; Apolipoprotein E knock-out (ApoE KO/ApoE−/−) mice; Apolipoproteins - metabolism; Apolipoproteins E - genetics; Brain - metabolism; Brain iron metabolism; Cytokines; Glutathione peroxidase 4 (Gpx4); Hepcidins - genetics; Homeostasis; Iron - metabolism; IRPs and hepcidin; Mice; Reactive oxygen species (ROS); Reactive Oxygen Species - metabolism; Receptors, Transferrin - genetics; Research Paper; TfR1 and Fpn1; AD and amyloid beta; Glutathione peroxidase 4 (Gpx4); Cytokines; Reactive oxygen species (ROS); Brain iron metabolism; TfR1 and Fpn1; Apolipoprotein E knock-out (ApoE KO/ApoE−/−) mice; IRPs and hepcidin; Apolipoprotein E knock-out (ApoE KO/ApoE(−/−)) mice
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2023.102779

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. 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. 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. 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.