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: AD and amyloid beta; Apolipoprotein E knock-out (ApoE KO/ApoE(−/−)) mice; Brain iron metabolism; Cytokines; Glutathione peroxidase 4 (Gpx4); IRPs and hepcidin; Reactive oxygen species (ROS); TfR1 and Fpn1.