Regulation of the Profile of Iron-Management Proteins in Brain Microvasculature

Abstract

The distribution of brain iron is heterogeneous, but the mechanism by which these regional differences are achieved and maintained is unknown. In this study, the authors test two hypotheses related to brain iron transport. The first is that there is regional variability in the profile of proteins associated with iron transport and storage in the brain microvasculature. The second hypothesis is that the iron status of the brain will dictate the response of the protein profile in the microvasculature to changes in systemic iron status. The profile analysis consists of transferrin (iron transport), ferritin (iron storage), transferrin receptor (iron uptake), and divalent metal transporter 1 (release of iron from endosomes). An additional protein involved in cellular iron efflux, ferroportin, was not detected in brain microvasculature. The results show that there are significantly higher levels of these proteins in the microvasculature from each area of the brain compared to a whole brain homogenate, but no regional differences within the microvasculature. The levels of ferritin observed in the microvasculature indicate that the microvascular endothelial cells have significant iron storage capacity. There are no significant changes in the regional protein profiles in response to systemic iron manipulation when brain iron status was normal. In contrast, in Belgrade rats, whose brain is iron deficient, the expression of both divalent metal transporter 1 and transferrin receptor was increased compared with control in almost all brain regions examined, but not transferrin or ferritin. These findings indicate that regional brain iron heterogeneity is not maintained by differences in microvascular iron-management protein levels. The results also indicate that brain iron status dictates the response of the microvascular protein profile to systemic iron manipulation.