The Role of a Common HFE Gene Variant in Brain Iron Accumulation

HFE is an essential protein for regulating iron transport into cells. Two common mutations of HFE, C282Y and H63D, result in loss of this regulation and cause accumulation of iron within the cell. The cellular iron accumulation can reach toxic levels. While much has been studied regarding the role of HFE in iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. In fact, it has long been believed that the brain is protected against iron overload by the blood‐brain barrier (BBB). Recently, however, our laboratory and others have correlated HFE gene variants with neurodegenerative diseases, specifically amyotrophic lateral sclerosis (ALS) and Alzheimer's Disease (AD). A critical review of historic literature, recent MRI studies and a novel more representative mouse model generated in our laboratory all suggest there is elevated iron in the brain associated with HFE gene variants. We generated a mouse model in which the wild‐type (WT) HFE gene is replaced by the H67D gene variant (mouse homologue of the human H63D gene variant). There are elevated levels of brain iron in 3 month old mice with the H67D mutation when compared to their controls, but this difference in levels is decreased at 6 months and no longer present by 12 months of age. Here, we performed an in vivo study to identify brain iron uptake and distribution patterns in 3 month old WT and H67D mice. After injection with 59 Fe‐transferrin, mice were sacrificed at 24 hours and 5 days post‐injection. 59 Fe levels measured in brain homogenate and isolated microvessels showed no significant differences between genotypes. There was, however, increased 59 Fe accumulation in the livers of H67D mice. This study makes two novel discoveries. First, there is iron accumulation in the microvessels in the brain supporting the concept put forth recently by our group that the BBB is not a conduit but a regulatory site for brain iron uptake. Secondly, the similar rate of uptake for iron in the HFE mutant mice, coupled with the increased amount of iron suggests that the activity of the HFE protein is limited at the BBB. The increased iron in the brain in the H67D mice may be the result of altered handling of the iron including decreased export. We cannot rule out the lack of difference in uptake is a compensatory process already in place because of the higher iron levels and this notion is under investigation. The apparent ability of the BBB, unlike the liver for example, to adapt to the HFE gene variant reinforces the importance of understanding the mechanisms and regulation of brain iron uptake and how the pathway is modulated in the diseased brain. Support or Funding Information This work was supported by NIH P01 AG021190 and P01 HD39386.