Endothelial cells are critical regulators of iron transport in a model of the human blood–brain barrier

Chiou, Brian; Neal, Emma H.; Bowman, Aaron B.; Lippmann, Ethan S.; Simpson, Ian A.; Connor, James R.

doi:10.1177/0271678x18783372

Cited by 90 publications

(122 citation statements)

References 62 publications

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“…We used our previously published methods for labeling Tf and FtH1 with 59 Fe (Duck et al ; Chiou et al ). Briefly, 59 Fe (Perkin Elmer, Waltham, MA, USA, #NEZ037500) was complexed with 1 mM nitriloacetic acid (NTA; Sigma, St Louis, MO, USA, #N0253), 0.5 M sodium bicarbonate (NaHCO 3 ), and 6.17 mM ferric chloride (FeCl 3 ) at a ratio of 100 µL NTA: 6.7 µL FeCl 3 : 23.3 µL NaHCO 3 : 50 µCi 59 FeCl 3 to create the 59 Fe‐NTA complex, adjusted for cases where greater or less than 50 µCi was necessary.…”

Section: Methodsmentioning

confidence: 99%

“…Classical studies of iron delivery to the brain have mainly focused on the ability of Tf to deliver iron both during development as well as in the adult brain (Fishman et al ; Taylor and Morgan ). However, we have recently demonstrated the ability for H‐ferritin (FtH1), to cross the BBB (Chiou et al ; Chiou et al ) and provide a substantial amount of iron into the brain (Fisher et al ). This is a significant departure from the established literature that posited FtH1 as simply an iron storage protein (Arosio et al ).…”

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confidence: 99%

“…Specifically, we determined if the presence of the H67D gene variant altered brain iron uptake during development. Moreover, given the evidence for FtH1 uptake in our cell culture models (Chiou et al ; Chiou et al ) and adult mice (Fisher et al ), we compared FtH1 iron delivery with Tf during development. We hypothesized that the H67D genotype and sex influences the relative levels of uptake of iron during development similar to that seen in our previous study in adults (Duck et al ; Wade et al ).…”

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confidence: 99%

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Transferrin and H‐ferritin involvement in brain iron acquisition during postnatal development: impact of sex and genotype

Chiou

Neely

McDevitt

et al. 2019

Journal of Neurochemistry

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Iron delivery to the developing brain is essential for energy and metabolic support needed for processes such as myelination and neuronal development. Iron deficiency, especially in the developing brain, can result in a number of long‐term neurological deficits that persist into adulthood. There is considerable debate that excess access to iron during development may result in iron overload in the brain and subsequently predispose individuals to age‐related neurodegenerative diseases. There is a significant gap in knowledge regarding how the brain acquires iron during development and how biological variables such as development, genetics, and sex impact brain iron status. In this study, we used a mouse model expressing a mutant form of the iron homeostatic regulator protein HFE, (Hfe H63D), the most common gene variant in Caucasians, to determine impact of the mutation on brain iron uptake. Iron uptake was assessed using 59Fe bound to either transferrin or H‐ferritin as the iron carrier proteins. We demonstrate that at postnatal day 22, mutant mice brains take up greater amounts of iron compared with wildtype. Moreover, we introduce H‐ferritin as a key protein in brain iron transport during development and identify a sex and genotype effect demonstrating female mutant mice take up more iron by transferrin, whereas male mutant mice take up more iron from H‐ferritin at PND22. Furthermore, we begin to elucidate the mechanism for uptake using immunohistochemistry to profile the regional distribution and temporal expression of transferrin receptor and T‐cell immunoglobulin and mucin domain 2, the latter is the receptor for H‐ferritin. These data demonstrate that sex and genotype have significant effects on iron uptake and that regional receptor expression may play a large role in the uptake patterns during development. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: .

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Transferrin and H‐ferritin involvement in brain iron acquisition during postnatal development: impact of sex and genotype

Chiou

Neely

McDevitt

et al. 2019

Journal of Neurochemistry

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“…Iron is the most abundant metal in the brain (Ward et al, 2014;Ashraf, Clark, & So, 2018). Iron delivery to the brain is essential for multiple neurological processes including myelination, neurotransmitter synthesis, and energy production (Chiou et al, 2018a), and brain iron status is consistently maintained and tightly regulated at the level of the BBB (Duck et al, 2018). Understanding the mechanism of transport of iron across the BBB therefore is crucial to address the impact both of iron deficiency on brain development and of excessive accumulation of iron in neurodegenerative diseases (Chiou et al, 2018a).…”

Section: Iron Transport Across the Blood-brain Barriermentioning

confidence: 99%

Brain iron transport

Qian

2019

Biological Reviews

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Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood–brain barrier, the blood–cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.

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“…The blood-brain barrier (BBB) is the unique structure in the brain that is different from other tissues and organs, which tightly regulates the movement of ions, molecules, and cells between the blood and the brain (Daneman and Prat, 2015). Thus, the endothelial cells of the BBB are the key site for regulating brain iron uptake, and the Tf/TfR1 pathway is the main brain iron absorption route depending on BBB (Duck et al, 2017;Chiou et al, 2019a;Qian and Ke, 2019). Research shows that Tf is the iron carrier that is responsible for delivering ferric iron to erythrocyte precursors and other tissues, but the ferrous iron must be oxidized to ferric iron by hephestin, a multi-copper ferroxidase enzyme, before it binds to Tf (Yiannikourides and Latunde-Dada, 2019).…”

Section: Brain Iron Metabolismmentioning

confidence: 99%

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

2020

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Iron is an essential transition metal for numerous biologic processes in mammals. Iron metabolism is regulated via several coordination mechanisms including absorption, utilization, recycling, and storage. Iron dyshomeostasis can result in intracellular iron retention, thereby damaging cells, tissues, and organs through free oxygen radical generation. Numerous studies have shown that brain iron overload is involved in the pathological mechanism of neurodegenerative disease including Alzheimer's disease (AD). However, the underlying mechanisms have not been fully elucidated. Ferroptosis, a newly defined iron-dependent form of cell death, which is distinct from apoptosis, necrosis, autophagy, and other forms of cell death, may provide us a new viewpoint. Here, we set out to summarize the current knowledge of iron metabolism and ferroptosis, and review the contributions of iron and ferroptosis to AD.

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Endothelial cells are critical regulators of iron transport in a model of the human blood–brain barrier

Cited by 90 publications

References 62 publications

Transferrin and H‐ferritin involvement in brain iron acquisition during postnatal development: impact of sex and genotype

Transferrin and H‐ferritin involvement in brain iron acquisition during postnatal development: impact of sex and genotype

Brain iron transport

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

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