Apolipoprotein E is required for brain iron homeostasis in mice

Abstract

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.

Keywords

• Apolipoprotein E knock-out (ApoE KO/ApoE−/−) mice
• Brain iron metabolism
• TfR1 and Fpn1
• IRPs and hepcidin
• AD and amyloid beta
• Reactive oxygen species (ROS)