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. 2018 Mar;38(3):540-548.
doi: 10.1177/0271678X17701949. Epub 2017 Mar 28.

A Role for Sex and a Common HFE Gene Variant in Brain Iron Uptake

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Free PMC article

A Role for Sex and a Common HFE Gene Variant in Brain Iron Uptake

Kari A Duck et al. J Cereb Blood Flow Metab. .
Free PMC article

Abstract

HFE (high iron) is an essential protein for regulating iron transport into cells. Mutations of the HFE gene result in loss of this regulation causing accumulation of iron within the cell. The mutated protein has been found increasingly in numerous neurodegenerative disorders in which increased levels of iron in the brain are reported. Additionally, evidence that these mutations are associated with elevated brain iron challenges the paradigm that the brain is protected by the blood-brain barrier. While much has been studied regarding the role of HFE in cellular iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. We investigated regulation of iron transport into the brain using a mouse model with a mutation in the HFE gene. We demonstrated that the rate of radiolabeled iron (59Fe) uptake was similar between the two genotypes despite higher brain iron concentrations in the mutant. However, there were significant differences in iron uptake between males and females regardless of genotype. These data indicate that brain iron status is consistently maintained and tightly regulated at the level of the blood-brain barrier.

Keywords: HFE; Iron; blood–brain barrier; brain development; sex.

Figures

Figure 1.
Figure 1.
Total brain iron in wild type and H67D/H67D mice at three months of age. Whole brains were harvested and then digested in HNO3. Total brain iron was then measured in the brains of H67D/H67D and wild type mice by atomic absorption. There was significantly more iron in the brain of H67D/H67D mice when compared to their wild type counterparts. Iron in H67D/H67D males was ∼37% higher than wild type males while iron in H67D/H67D females was ∼61% higher than wild type females. n = 5/group. ***p < 0.001, ****p < 0.0001.
Figure 2.
Figure 2.
59Fe accumulation in the livers of wild type and H67D/H67D mice. Iron was injected intravenously and then the livers were collected, weighed, and radioactivity was measured. (a) At 24 h after injection, H67D/H67D females exhibited significantly more 59Fe retention in the liver, but no other changes were observed. (b) At five days after injection, there were no significant differences in 59Fe liver accumulation across genotypes, but there was significantly more 59Fe retained in the liver of female mice when compared to their male counterparts. *p < 0.05.
Figure 3.
Figure 3.
59Fe accumulation in whole brain. Iron was injected intravenously and then the brains collected, homogenized and radioactivity was measured in the whole brain prior to making fractions. (a) At 24 h after injection with 59Fe-Tf, no significant sex or genotype effects were observed. (b) At five days after injection with 59Fe-Tf, there was significantly more 59Fe present in the brains of female mice than in the brains of male mice for both genotypes studied. (c) Changes in 59Fe between the 24-h and five-day time points were calculated. Wild type females exhibited significantly less change than the wild type males, which had reduced 59Fe. *p < 0.05.
Figure 4.
Figure 4.
59Fe accumulation in an isolated cortical brain fraction. The cortical fraction was generated by performing a capillary depletion on whole brain homogenates. Radioactivity was then measured in this brain fraction. (a) After 24 h, no significant sex or genotype effects were observed. (b) Five days after injection, females for both genotypes exhibited significantly more cortical 59Fe accumulation when compared to males within the same genotype. (c) There were no significant differences in the change seen in cortical brain levels of 59Fe. *p < 0.05.
Figure 5.
Figure 5.
59Fe accumulation in a myelin-containing brain fraction. The brain homogenate was processed by density centrifugation to isolate the myelin-containing fraction of the brain. This fraction was then weighed and radioactivity was measured. (a) No significant sex or genotype effects were seen at 24 h after injection. (b) At five days after injection, however, there was significantly more 59Fe in the myelin-containing brain fraction of females when compared to males within the same genotype. (c) The change in iron associated with the myelin-containing fraction was calculated. The wild type males exhibited a greater reduction in 59Fe over the five-day time period than wild type females or H67D/H67D males. *p < 0.05.
Figure 6.
Figure 6.
59Fe accumulation in the brain microvasculature. Microvessels were isolated from the brain and homogenized. Total protein was measured and the radioactivity was measured. (a) Within 24 h after injection, the brain microvasculature accumulated measurable levels of 59Fe. (b) After five days, the brain microvasculature retained 59Fe. (c) The microvasculature exhibited almost no change in 59Fe over the five-day time course studied here, indicating its ability to retain iron and function as an iron reservoir.

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