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Retinal iron accumulation has been implicated in the pathogenesis of age-related macular degeneration (AMD) and other neurodegenerative diseases. The retina and the brain are protected from the systemic circulation by the blood retinal barrier (BRB) and blood brain barrier (BBB), respectively. Iron levels within the retina and brain need to be tightly regulated to prevent oxidative injury. The method of iron entry through the retina and brain vascular endothelial cells (r&bVECs), an essential component of the BRB and BBB, is not fully understood. However, localization of the cellular iron exporter, ferroportin (Fpn), to the abluminal membrane of these cells, leads to the hypothesis that Fpn may play an important role in the import of iron across the BRB and BBB. To test this hypothesis, a mouse model with deletion of Fpn within the VECs in both the retina and the brain was developed through tail vein injection of AAV9-Ple261(CLDN5)-icre to both experimental Fpnf/f, and control Fpn+/+ mice at P21. Mice were aged to 9 mo and changes in retinal and brain iron distribution were observed. In vivo fundus imaging and quantitative serum iron detection were used for model validation. Eyes and brains were collected for immunofluorescence. Deletion of Fpn from the retinal and brain VECs leads to ferritin-L accumulation, an indicator of elevated iron levels, in the retinal and brain VECs. This occurred despite lower serum iron levels in the experimental mice. This result suggests that Fpn normally transfers iron from retinal and brain VECs into the retina and brain. These results help to better define the method of retina and brain iron import and will increase understanding of neurodegenerative diseases involving iron accumulation.

Original publication

DOI

10.1016/j.exer.2019.107728

Type

Journal article

Journal

Exp Eye Res

Publication Date

16/07/2019

Keywords

AMD, Age-related macular degeneration (AMD), BBB, BRB, Cp, Dmt1, Ferritin, Ferroportin, Fpn, Ft-L, Hepc, Hepcidin, Heph, Iron, NSR, NTBI, Ple, Pleiades Promoter Project, RPE, Retina, Retinal vascular endothelium, TBI, Tf, TfR, age-related macular degeneration, bVECs, blood-brain barrier, blood-retinal barrier, brain vascular endothelial cells, ceruloplasmin, divalent metal transporter 1, ferritin-L, ferroportin, hephaestin, neurosensory retina, non-transferrin bound iron, rVECs, retinal pigment epithelium, retinal vascular endothelial cells, transferrin, transferrin bound iron, transferrin receptor