Iron regulation in the brain: Histochemical, biochemical, and molecular considerations

Despite recognition that iron is important for normal neurological function, the proteins involved in maintaining iron homeostasis within the brain have until recently received little attention. In the past few years, studies aimed at determining both general and cellular control of iron in the brain have increased. Histological studies indicate that maintenance of iron homeostasis in the brain is the responsibility of neuroglia and possibly the choroid plexus. Transferrin, the iron transport protein, has been found predominantly in oligodendrocytes in the brain and in myelinating Schwann cells in the peripheral nervous system. The messenger RNA for transferrin is located in the brain in oligodendrocytes and the choroid plexus. Most of the transferrin protein and transcript expression in the brain is dependent on the presence of a mature population of oligodendrocytes. Transferrin is also involved in the transport of iron across the blood-brain barrier via transferrin receptors on brain capillary endothelial cells. The transferrin receptor is also present on cells within the brain. Ferritin, the iron storage protein, and iron are found in the brain in oligodendrocytes and microglia. Additional cells in which iron and ferritin are found are tanycytes, which are associated with the third ventricle. This latter observation raises interesting possibilities regarding the transport of iron from cerebrospinal fluid into the brain. The high iron requirement of the brain coupled with the high susceptibility of the brain to iron-generated peroxidative damage requires stringent regulation of the availability of iron. Consequently, the iron regulatory proteins are central to understanding mechanisms controlling iron-dependent activity at the cellular level, as well as protection of the brain from oxidative damage. The behavior of brain iron regulatory proteins will be a significant factor in future studies of the neurological diseases resulting from brain iron imbalance. We review the contributions of our laboratory to this field over the past 6 years, discuss current projects, and suggest future directions for study.