Transferrin and Iron Uptake by the Brain: Effects of Altered Iron Status

Taylor, Eve M.; Crowe, Andrew; Morgan, Evan H.

doi:10.1111/j.1471-4159.1991.tb06355.x

Cited by 134 publications

(90 citation statements)

References 43 publications

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“…Also, cellular replication in the brain of the rat, especially in capillary and glial cells, occurs most rapidly during the first 2-3 weeks of life [27,28]. With respect to iron supply it was found that variations in dietary iron lead to changes in iron and transferrin uptake by the brain, increasing with iron depletion and decreasing with iron loading [29]. However, age-dependent changes in transferrin uptake were not eliminated.…”

Section: Iron Transport Into the Developing Brainmentioning

confidence: 88%

Mechanism and Developmental Changes in Iron Transport across the Blood-Brain Barrier

Morgan

Moos

2002

Dev Neurosci

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Transferrin and iron uptake by the brain were measured using [⁵⁹Fe-¹²⁵I]transferrin injected intravenously in rats aged from 15 days to 22 weeks. The values for both decreased with age. In rats aged 18 and 70 days the uptake was measured at short time intervals after the injection. When expressed as the volume of distribution (Vd), which represents the volume of plasma from which the transferrin and iron were derived, the results for iron were greater than those of transferrin as early as 7 min after injection and the difference increased rapidly with time, especially in the younger animals. A very similar time course was found for uptake by bone marrow (femurs) where iron uptake involves receptor-mediated endocytosis of Fe-transferrin, release of iron in the cell and recycling of apo-transferrin to the blood. It is concluded that, during transport of transferrin-bound plasma iron into the brain, a similar process occurs in brain capillary endothelial cells (BCECs) and that transcytosis of transferrin into the brain interstitium is only a minor pathway. Also, the high rate of iron transport into the brain in young animals, when iron requirements are high due to rapid growth of the brain, is a consequence of the level of expression and rate of recycling of transferrin receptors on BCECs. As the animal and brain mature both decrease.

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Section: Iron Transport Into the Developing Brainmentioning

confidence: 88%

Mechanism and Developmental Changes in Iron Transport across the Blood-Brain Barrier

Morgan

Moos

2002

Dev Neurosci

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“…Following translocation to early endosomes, iron dissociates from transferrin and is transported to the cytoplasm or directly to the mitochondria. In the brain, iron uptake mediated by TfR participates in iron transport through the blood-brain barrier (6), and the density of TBI-binding sites correlates well with the regional distribution of TfR expression on the luminal surface of endothelial cells. However, TBI-binding sites and TfR expression only loosely correlate with the final steady-state distribution of iron (7).…”

Section: Dopaminergic Cell Death In the Substantia Nigra (Sn) Is Centmentioning

confidence: 96%

Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease

Salazar

Mena²,

Hunot³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

369

320

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Dopaminergic cell death in the substantia nigra (SN) is central toParkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/ Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.iron ͉ oxidative stress ͉ substantia nigra ͉ MPTP ͉ 6-hydroxydopamine P arkinson's disease (PD) is the most frequent neurodegenerative movement disorder worldwide. It is characterized by a preferential degeneration of dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous cytoplasmic inclusions, called Lewy bodies, in the remaining DNs (1). Apart from rare, inherited forms of the disease, the etiology of PD remains unknown. Nevertheless, it seems clear that aging, mitochondrial dysfunction, inflammation, and oxidative imbalance are among the factors contributing to its pathophysiology.A rise in iron content localized in glial cells and DNs of the SNpc has been reported in patients with PD (2, 3). This increase of iron is thought to contribute to DN cell death by catalyzing the production of hydroxyl radicals from hydrogen peroxide, a byproduct in dopamine catabolism, and by promoting fibril formation of ␣-synuclein, the most abundant component of Lewy bodies (4). Neuroprotection achieved by pharmacological or genetic chelation of iron in animal models of PD supports the role of iron in neuronal degeneration in PD (5). Yet, the mechanisms underlying the iron increase have not been elucidated. Transferrin-bound iron (TBI) can be incorporated into cells by an endocytotic process, which is initiated by transferrin receptor 1 (TfR1) ligand binding. Following translocation to early endosomes, iron dissociates from transferrin and is transported to the cytoplasm or directly to the mitochondria. In the brain, iron uptake mediated by TfR participates in iron transport through the blood-brain barrier (6), and the density of TBI-binding sites correlates well with the regional distribution of TfR expression on the luminal surface of endothelial cells. However, TBI-binding sites and TfR expression only loosely correlate with the final steady-state distribution of iron (7). Moreover, TBI-binding sites are decreased in nu...

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“…The brain has two potential mechanisms to increase iron delivery to iron-starved neurons. The more general mechanism would be to increase total brain iron delivery from the serum via the blood-brain and the blood-CSF-brain interfaces (10,26). This mechanism seems to be the normal response of the more mature animal where brain iron uptake increases 2-fold in response to dietary iron deficiency (26).…”

Section: Discussionmentioning

confidence: 99%

“…The more general mechanism would be to increase total brain iron delivery from the serum via the blood-brain and the blood-CSF-brain interfaces (10,26). This mechanism seems to be the normal response of the more mature animal where brain iron uptake increases 2-fold in response to dietary iron deficiency (26). This process would be dependent on the vascular endothelial cell of the blood-brain barrier, the choroid plexus epithelial cell of the blood-CSF barrier, and the ependymal cell of the CSF-brain barrier being able to sense the total iron status of the brain.…”

Section: Discussionmentioning

confidence: 99%

Iron Deficiency Alters Iron Regulatory Protein and Iron Transport Protein Expression in the Perinatal Rat Brain

et al. 2003

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Iron plays an important role in numerous vital enzyme systems in the perinatal brain. The membrane proteins that mediate iron transport [transferrin receptor (TfR) and divalent metal transporter 1 (DMT-1)] and the iron regulatory proteins (IRP-1 and IRP-2) that stabilize their mRNAs undergo regional developmental changes in the iron-sufficient rat brain between postnatal day (P) 5 and 15. Perinatal iron deficiency (ID) affects developing brain regions nonhomogeneously, suggesting potential differences in regional iron transporter and regulatory protein expression. The objective of the study was to determine the effect of perinatal ID on regional expression of IRP-1, IRP-2, TfR, and DMT-1 in the developing rat brain. Gestationally iron-deficient Sprague Dawley rat pups were compared with iron-sufficient control pups at P10. Serial 12-coronal sections of fixed frozen brain from pups on P10 were assessed by light microscopy for IRP-1, IRP-2, DMT-1, and TfR localization. Iron is essential for normal CNS growth and development because it forms an important component of hemoproteins and enzymes involved in neuronal oxidative metabolism, neurotransmitter synthesis, and myelin synthesis (1). Iron deficiency (ID) during late fetal and early postnatal life in humans (2, 3) and in animal models is associated with cognitive impairments that persist despite iron repletion (4). These deficits are presumably due to alterations in iron-based neuronal cellular processes that occur during a period of rapid brain growth and its associated high iron demand (5).ID during the perinatal period also results in regionalization of functional brain iron (6 -8). Regionalization suggests that the brain has a mechanism for sensing iron requirements and for prioritizing iron to high-need areas. We have previously shown that a 40% decrease in total brain iron content in the perinatal rat results in differential regional losses of cytochrome c oxidase (CytOx), an iron-containing enzyme, with more marked deficits noted in the hippocampus and prefrontal cortex than in the striatum on postnatal day (P) 10 (6). The preferential loss of hippocampal CytOx in our model is consistent with deficits in the neural circuits underlying recogni- ABSTRACT 800

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Transferrin and Iron Uptake by the Brain: Effects of Altered Iron Status

Cited by 134 publications

References 43 publications

Mechanism and Developmental Changes in Iron Transport across the Blood-Brain Barrier

Mechanism and Developmental Changes in Iron Transport across the Blood-Brain Barrier

Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease

Iron Deficiency Alters Iron Regulatory Protein and Iron Transport Protein Expression in the Perinatal Rat Brain

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