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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron is essential for virtually all types of cells and organisms. The significance of the iron for brain function is reflected by the presence of receptors for transferrin on brain capillary endothelial cells. The transport of iron into the brain from the circulation is regulated so that the extraction of iron by brain capillary endothelial cells is low in iron-replete conditions and the reverse when the iron need of the brain is high as in conditions with iron deficiency and during development of the brain. Whereas there is good agreement that iron is taken up by means of receptor-mediated uptake of iron-transferrin at the brain barriers, there are contradictory views on how iron is transported further on from the brain barriers and into the brain extracellular space. The prevailing hypothesis for transport of iron across the BBB suggests a mechanism that involves detachment of iron from transferrin within barrier cells followed by recycling of apo-transferrin to blood plasma and release of iron as non-transferrin-bound iron into the brain interstitium from where the iron is taken up by neurons and glial cells. Another hypothesis claims that iron-transferrin is transported into the brain by means of transcytosis through the BBB. This thesis deals with the topic "brain iron homeostasis" defined as the attempts to maintain constant concentrations of iron in the brain internal environment via regulation of iron transport through brain barriers, cellular iron uptake by neurons and glia, and export of iron from brain to blood. The first part deals with transport of iron-transferrin complexes from blood to brain either by transport across the brain barriers or by uptake and retrograde axonal transport in motor neurons projecting beyond the blood-brain barrier. The transport of iron and transport into the brain was examined using radiolabeled iron-transferrin. Intravenous injection of [59Fe-125]transferrin led to an almost two-fold higher accumulation of 59Fe than of [125I]transferrin in the brain. Some of the 59Fe was detected in CSF in a fraction less than 30 kDa (III). It was estimated that the iron-binding capacity of transferrin in CSF was exceeded, suggesting that iron is transported into the brain in a quantity that exceeds that of transferrin. Accordingly, it was concluded that the paramount iron transport across the BBB is the result of receptor-mediated endocytosis of iron-containing transferrin by capillary endothelial cells, followed by recycling of transferrin to the blood and transport of non-transferrin-bound iron into the brain. It was found that retrograde axonal transport in a cranial motor nerve is age-dependent, varying from almost negligible in the neonatal brain to high in the adult brain. The principle sources of extracellular transferrin in the brain are hepatocytes, oligodendrocytes, and the choroid plexus. As the passage of liver-derived transferrin into the brain is restricted due to the BBB, other candidates for binding iron in the interstitium should be considered. In vitro studies have revealed secretion of transferrin from the choroid plexus and oligodendrocytes. The second part of the thesis encompasses the circulation of iron in the extracellular fluids of the brain, i.e. the brain interstitial fluid and the CSF. As the latter receives drainage from the interstitial fluid, the CSF of the ventricles can be considered a mixture of these fluids, which may allow for analysis of CSF in matters that relate to the brain interstitial fluid. As the choroid plexus is known to synthesize transferrin, a key question is whether transferrin of the CSF might play a role for iron homeostasis by diffusing from the ventricles and subarachnoid space to the brain interstitium. Intracerebroventricular injection of [59Fe125I]transferrin led to a higher accumulation of 59Fe than of [125I]transferrin in the brain. Except for uptake and axonal transport by certain neurons with access to the ventricular CSF, both iron and transferrin were, however, restricted to areas situated in close proximity to the ventricular and pial surfaces. In particular, transferrin injected into the ventricles was never observed in regions distant from the CSF. It was concluded that choroid plexus-derived transferrin is not likely to play a significant role for binding and transporting iron in the brain interstitium. Transferrin secretion from oligodendrocytes probably plays the key role in this process. In the third part of the thesis, the uptake of iron by neurons devoid of projections beyond the blood-brain barrier and glia is addressed. Given the fact that the demonstration of plasma proteins in brain sections can be hampered by several methodological factors, a mapping of the cellular distribution of transferrin in the brain was performed employing extensive use of tissue-processing and staining protocols. In order to aid in the understanding of cellular iron uptake in the intact brain, attempts were made to identify iron, transferrin, and transferrin receptors at the light microscopic level. Consistent with the widespread distribution of transferrin receptors in neurons, the ligand transferrin was also found in neurons throughout the CNS. When examined at high resolution, transferrin was found to be distributed to the cytoplasm of neurons, exhibiting a dotted appearance, which is probably consistent with a distribution in the endosomallysosomal system. In contrast to the consistent presence of transferrin receptors on neurons, it was not possible to detect transferrin receptors on glial cells. Related to these observations, the presence of non-transferrin-bound iron in the brain suggests that glial cells may take it up by a mechanism that does not involve the transferrin receptor. The widespread distribution of ferritin in glial cells clearly indicates that the glial cells acquire iron. Dietary iron-overload did not change the distribution of transferrin receptors or ferritin in the brain. By contrast, iron deficiency altered the cellular content of these proteins so that transferrin receptors were higher and ferritin lower. The transport of iron from brain to blood was addressed in the last part of the thesis. It was found that in the case of iron and transferrin, there is no evidence showing other significant routes of transport from the brain extracellular fluid into the blood than drainage to the ventricular system followed by export to the blood via the arachnoid villi. The turnover of transferrin in the CSF was found to be very high. For reasons mentioned above, transferrin of the CSF is of little significance for transport and cellular delivery of iron to transferrin receptor-expressing neurons. Instead, transferrin of the CSF probably plays a significant role for neutralization and export to the blood of metals, including iron. Once appearing in blood, transferrin of the CSF was degraded at the same rate as intravenously injected transferrin, which indicates that the transferrin of CSF is not altered to an extent that changes its catabolism during the passage from CSF to blood plasma. The metabolism of iron in the developing brain was found to differ markedly when compared to that of the adult brain. A developing regulated transfer of iron to the brain was reflected morphologically by a higher content of transferrin receptors and non-heme iron in endothelial cells of the developing rat brain than in the adult. Neurons had a very low level of transferrin receptors. After about 20 days of age, iron transport into the brain decreased rapidly, and transferrin receptors appeared on neurons. Iron and transferrin injected into the ventricular system of the developing brain were much more widely distributed in the brain parenchyma than in the adult brain. This high accumulation of substances injected into the ventricles in young animals is probably due to the lower rate of production and turnover of CSF, which will increase the time available for diffusion of proteins into the brain parenchyma, thus giving neurons of the developing brain the opportunity to take up transferrin originating from the CSF.
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PMID:Brain iron homeostasis. 1255 65

Restless legs syndrome is common in patients with multiple sclerosis but has not been reported as occurring due to an acute, inflammatory, demyelinating attack. Restless legs syndrome is known to be related to low brain iron levels. Multiple sclerosis has been associated with the abnormal accumulation of iron in the chronic, progressive phase of axonal degeneration. Iron deficiency may play a role in demyelination. This suggests that restless legs syndrome may be caused by the inflammatory, demyelinating component of multiple sclerosis rather than axonal degeneration. The author presents a case of self-limited restless legs syndrome occurring as an acute attack of multiple sclerosis, supporting the notion that inflammatory demyelination is the underlying pathophysiology of restless legs syndrome in multiple sclerosis.
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PMID:Restless legs syndrome presenting as an acute exacerbation of multiple sclerosis. 2209 45

Iron is critical in multiple aspects of CNS development, but its role in neurodevelopment--the ability of iron deficiency to alter normal development--is difficult to dissociate from the effects of anemia. We developed a novel dietary restriction model in the rat that allows us to study the effects of iron deficiency in the absence of severe anemia. Using a combination of auditory brainstem response analyses (ABR) and electron microscopy, we identified an unexpected impact of nonanemic iron deficiency on axonal diameter and neurofilament regulation in the auditory nerve. These changes are associated with altered ABR latency during development. In contrast to models of severe iron deficiency with anemia, we did not find consistent or prolonged defects in myelination. Our data demonstrate that iron deficiency in the absence of anemia disrupts normal development of the auditory nerve and results in altered conduction velocity.
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PMID:Iron deficiency disrupts axon maturation of the developing auditory nerve. 2249 56

Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.
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PMID:Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice. 2698 1

Early-life iron deficiency results in long-term abnormalities in cognitive function and affective behavior in adulthood. In preclinical models, these effects have been associated with long-term dysregulation of key neuronal genes. While limited evidence suggests histone methylation as an epigenetic mechanism underlying gene dysregulation, the role of DNA methylation remains unknown. To determine whether DNA methylation is a potential mechanism by which early-life iron deficiency induces gene dysregulation, we performed whole genome bisulfite sequencing to identify loci with altered DNA methylation in the postnatal day (P) 15 iron-deficient (ID) rat hippocampus, a time point at which the highest level of hippocampal iron deficiency is concurrent with peak iron demand for axonal and dendritic growth. We identified 229 differentially methylated loci and they were mapped within 108 genes. Among them, 63 and 45 genes showed significantly increased and decreased DNA methylation in the P15 ID hippocampus, respectively. To establish a correlation between differentially methylated loci and gene dysregulation, the methylome data were compared to our published P15 hippocampal transcriptome. Both datasets showed alteration of similar functional networks regulating nervous system development and cell-to-cell signaling that are critical for learning and behavior. Collectively, the present findings support a role for DNA methylation in neural gene dysregulation following early-life iron deficiency.
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PMID:Dysregulation of Neuronal Genes by Fetal-Neonatal Iron Deficiency Anemia Is Associated with Altered DNA Methylation in the Rat Hippocampus. 3113 89