Identification of a Novel Route of Iron Transcytosis across the Mammalian Blood‐Brain Barrier

Moroo, Iku; Ujiie, Maki; Walker, Brandie; Tiong, Jacqueline; Vitalis, Timothy Z.; Karkan, Delara; Gabathuler, Reinhard; Moise, Alexander R.; Jefferies, Wilfred A.

doi:10.1038/sj.mn.7800213

Cited by 31 publications

(37 citation statements)

References 30 publications

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“…Transport of iron across the blood-brain barrier (BBB) is complex due to the restricted diffusion of transferrin from blood to brain. One study demonstrated that iron is transported across the BBB at a faster rate than transferrin [26], supporting the idea that non-transferrin-bound iron enters the brain and that much of the serum transferrin is effluxed or transcytosed out of the brain [27,28]. To allow for immobilization of this potentially free iron species, oligodendrocytes and choroid plexus cells produce transferrin within the brain [29].…”

Section: Embryonic Neuronal Developmentmentioning

confidence: 94%

“…Studies in hypotransferrinemic mice have shown that non-transferrin-bound iron readily crosses the BBB at low serum transferrin concentrations [34] arguing for the potential presence of other proteins for iron transport across the BBB [28]. Upon entry into the brain iron is likely to become rapidly bound by brain transferrin, but the iron binding capacity within the cerebrospinal fluid is low for a number of reasons that include low transferrin concentrations [35], high concentrations of ascorbic acid (maintaining iron in its reduced form), and low concentrations of ceruloplasmin, a ferroxidase that aids transferrin binding [35,36].…”

Section: Embryonic Neuronal Developmentmentioning

confidence: 99%

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Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Gaasch,

Lockman,

Geldenhuys

et al. 2007

Neurochem Res

185

111

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Iron accumulation or iron overload in brain is commonly associated with neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, and also plays a role in cellular damage following hemorrhagic stroke and traumatic brain injury. Despite the brain's highly regulated system for iron utilization and metabolism, these disorders often present following disruptions within iron metabolic pathways. Such dysregulation allows saturation of proteins involved in iron transport and storage, and may cause an increase in free ferrous iron within brain leading to oxidative damage. Not only do astrocytes, neurons, and brain endothelial cells serve unique purposes within the brain, but their individual cell types are equipped with distinct protective mechanisms against iron-induced injury. This review evaluates iron metabolism within the brain under homeostatic and pathological conditions and focuses on the mechanism(s) of brain cellular iron toxicity and differential responses of astrocytes, neurons, and brain vascular endothelial cells to excessive free iron.

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Section: Embryonic Neuronal Developmentmentioning

confidence: 94%

Section: Embryonic Neuronal Developmentmentioning

confidence: 99%

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Gaasch,

Lockman,

Geldenhuys

et al. 2007

Neurochem Res

185

111

View full text Add to dashboard Cite

show abstract

“…However, since the BBB limits the passage of large molecules, the transendothelial transport of serum transferrin-iron in the brain in vivo is still controversial. A role of p97 (also known as melanotransferrin) in the transfer of iron across the BBB and in iron homeostasis under physiological conditions has been reported (Moroo et al 2003).…”

Section: Transcytosis Is a Fast Selective And Tightly Regulated Promentioning

confidence: 99%

Endothelial transcytosis in health and disease

Simionescu¹,

Popov²,

Sima³

2008

Cell Tissue Res

112

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The visionaries predicted the existence of transcytosis in endothelial cells; the cell biologists deciphered its mechanisms and (in part) the molecules involved in the process; the cell pathologists unravelled the presence of defective transcytosis in some diseases. The optimistic perspective is that transcytosis, in general, and receptor-mediated transcytosis, in particular, will be greatly exploited in order to target drugs and genes to exclusive sites in and on endothelial cells (EC) or underlying cells. The current recognition that plasmalemmal vesicles (caveolae) are the vehicles involved in EC transcytosis has moved through various phases from initial considerations of caveolae as unmovable sessile non-functional plasmalemma invaginations to the present identification of a multitude of molecules and a crowd of functions associated with these ubiquitous structures of endothelial and epithelial cells. Further understanding of the molecular machinery that precisely guides caveolae through the cells so as to reach the target membrane (fission, docking, and fusion), to avoid lysosomes, or on the contrary, to reach the lysosomes, and discharge the cargo molecules will assist in the design of pathways that, by manipulating the physiological route of caveolae, will carry molecules of choice (drugs, genes) at controlled concentrations to precise destinations.

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“…injected sMTf accumulated in the brain although to a lesser extent than transferrin [292]. Beliveau’s group and others demonstrated that recombinant human MTf passed into the brain across BBB at a high rate via LRP1 receptor-mediated pathway [267, 293]. Owing to a very low level in the blood and fast rate of transcytosis across the BBB, MTf could be used as a carrier for drug delivery to the brain.…”

Section: Chemical Modification Of Proteins For Cns Deliverymentioning

confidence: 99%

Agile delivery of protein therapeutics to CNS

Xiang

Manickam

Brynskikh

et al. 2014

Journal of Controlled Release

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A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics.

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Identification of a Novel Route of Iron Transcytosis across the Mammalian Blood‐Brain Barrier

Abstract: These data support the idea that p97 is an important iron transporter across the blood-brain barrier in normal physiology and possibly in neurodegenerative diseases, such as Alzheimer disease, in which iron homeostasis in the brain becomes disrupted.

Cited by 31 publications

References 30 publications

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

Endothelial transcytosis in health and disease

Agile delivery of protein therapeutics to CNS

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