Elsevier

Seminars in Pediatric Neurology

Volume 13, Issue 3, September 2006, Pages 142-148
Seminars in Pediatric Neurology

Brain Iron Metabolism

https://doi.org/10.1016/j.spen.2006.08.002 Get rights and content

Brain iron uptake is regulated by the expression of transferrin receptor 1 in endothelial cells of the blood-brain barrier. Transferrin-bound iron in the systemic circulation is endocytosed by brain endothelial cells, and elemental iron is released to brain interstitial fluid, likely by the iron exporter, ferroportin. Transferrin synthesized by oligodendrocytes in the brain binds much of the iron that traverses the blood-brain barrier after oxidation of the iron, most likely by a glycophosphosinositide-linked ceruloplasmin found in astrocytic foot processes that ensheathe brain endothelial cells. Neurons acquire iron from diferric transferrin, but it is less clear how glial cells acquire iron. In aging mammals, iron accumulates in the basal ganglia, and iron accumulation is believed to contribute to neurodegenerative diseases, including Parkinson and Alzheimer disease. Here we consider the possibility that iron accumulations, which are often thought to facilitate free radical generation and oxidative damage, may contain insoluble iron that is unavailable for cellular use, and the pathology associated with iron accumulations may result from functional iron deficiency in some diseases.

Section snippets

How Does Iron Cross the Blood-Brain Barrier and Move Within the CNS?

For many years, it was believed that iron entered the brain mainly during infancy before the blood-brain barrier matured. However, in the last decade, it has become apparent that brain-iron uptake is mediated by endothelial TfR expression in the blood-brain barrier of adult animals, and this TfR expression on the luminal endothelial surface is regulated by the iron status of the CNS. The blood-brain barrier is an unusual structure composed of endothelial cells, a basal lamina, pericytes, and

Iron Redistribution With the Brain

After initial uptake in the brain, iron redistributes into various areas of the brain,68, 69 but the mechanisms by which iron redistributes in the brain are poorly understood. Studies in hypotransferrinemic mice suggest that redistribution of iron depends on the presence of intact Tf in brain interstitial fluid.70 As previously stated, Tf synthesized by oligodendrocytes does not return to the systemic circulation,71 presumably because CNS Tf cannot cross the tight epithelial cells of the

Misregulation of Brain Iron Metabolism and Neurodegeneration

In addition to the observation that iron accumulates abnormally in the brain of patients with sporadic Parkinson and Alzheimer diseases, abnormal accumulations of iron are also found in diseases with known genetic causes, including aceruloplasminemia,75 neurodegeneration with brain iron accumulation,76 and neuroferritinopathy.77 The usual hypothesis associated with these diseases is that abnormal accumulations of iron lead to increased formation of reactive oxygen species because ferrous iron

Future Directions

The axis that governs brain iron homeostasis has been partially described because it seems clear that endothelial TfR determines how much iron the brain will absorb. However, it is unclear how the brain and spinal cord gauge iron status and communicate this information to the blood brain barrier. To identify candidates for this role, the cells that express TfR2 should be identified because cells that express TfR2 could be functionally similar to hepatocytes. In addition, identifying the site of

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    Supported by the intramural program of the National Institute of Child Health and Human Development.

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