Cellular management of iron in the brain

All organs including the brain contain iron, and the proteins involved in iron uptake (transferrin and transferrin receptor) and intracellular storage (ferritin). However, because the brain resides behind a barrier and has a heterogeneous population of cells, there are aspects of its iron management that are unique. Iron management, the timely delivery of appropriate amounts of iron, is crucial to normal brain development and function. Mismanagement of cellular iron can result not only in decreased metabolic activity but increased vulnerability to oxidative damage. There is regional specificity in cell deposition of iron and the iron regulatory proteins. However, the sequestration of iron in the brain seems primarily the responsibility of oligodendrocytes, as these cells contain most of the stainable iron in the brain. Transferrin, the iron-mobilizing protein, is also found predominantly in these cells. The transferrin receptor is abundantly expressed on blood vessels, large neurons in the cortex, striatum, and hippocampus, and is also present on oligodendrocytes and astrocytes. Ferritin, the intracellular iron storage protein, consists of 2 subunits which are functionally distinct, and we provide evidence in this report that the cellular distribution of the ferritin subunits is also distinct. In addition, changes in the cellular distribution of iron and its associated regulatory proteins occur in Alzheimer's disease. Neuritic plaques contain relatively large amounts of stainable iron, and the surrounding cells robustly immunostain for ferritin and the transferrin receptor. Analysis of the cellular distribution of iron indicates the different levels of requirement of iron in the brain by different cell types and should ultimately elucidate how cells acquire and maintain this essential component of oxidative metabolism. In addition, changes in the ability of cells to deliver and manage iron may provide insight into altered metabolic activity with age and disease as well as identify cell populations at risk for iron-induced oxidative stress.