Ferroportin and Exocytoplasmic Ferroxidase Activity Are Required for Brain Microvascular Endothelial Cell Iron Efflux

McCarthy, Ryan C.; Kosman, Daniel J.

doi:10.1074/jbc.m113.455428

Cited by 71 publications

(80 citation statements)

References 41 publications

(67 reference statements)

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“…This conversion requires the presence of a soluble ferroxidase and ceruloplasmin has recently been proposed as a potential candidate by McCarthy and Kosman. 38 Additional support for a role for ceruloplasmin is provided by the observation in a mouse model of aceruloplasminemia, in which ferritin expression is increased in astrocytes, suggesting that these cells have accumulated iron. The mechanism by which iron accumulates in astrocytes is not known; they do not express TfRs, but have been shown to express DMT1.…”

Section: Discussionmentioning

confidence: 99%

A Novel Model for Brain Iron Uptake: Introducing the Concept of Regulation

Simpson

Ponnuru

Klinger

et al. 2014

J Cereb Blood Flow Metab

114

165

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Neurologic disorders such as Alzheimer's, Parkinson's disease, and Restless Legs Syndrome involve a loss of brain iron homeostasis. Moreover, iron deficiency is the most prevalent nutritional concern worldwide with many associated cognitive and neural ramifications. Therefore, understanding the mechanisms by which iron enters the brain and how those processes are regulated addresses significant global health issues. The existing paradigm assumes that the endothelial cells (ECs) forming the blood-brain barrier (BBB) serve as a simple conduit for transport of transferrin-bound iron. This concept is a significant oversimplification, at minimum failing to account for the iron needs of the ECs. Using an in vivo model of brain iron deficiency, the Belgrade rat, we show the distribution of transferrin receptors in brain microvasculature is altered in luminal, intracellular, and abluminal membranes dependent on brain iron status. We used a cell culture model of the BBB to show the presence of factors that influence iron release in non-human primate cerebrospinal fluid and conditioned media from astrocytes; specifically apo-transferrin and hepcidin were found to increase and decrease iron release, respectively. These data have been integrated into an interactive model where BBB ECs are central in the regulation of cerebral iron metabolism.

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Section: Discussionmentioning

confidence: 99%

A Novel Model for Brain Iron Uptake: Introducing the Concept of Regulation

Simpson

Ponnuru

Klinger

et al. 2014

J Cereb Blood Flow Metab

114

165

View full text Add to dashboard Cite

show abstract

“…59 Fe entry into the brains of rats intravenously injected with 59 Fe- 125 I-Tf reached a maximum at day 15 and significantly decreased thereafter with minimal accumulation observed in brains of 8 week old rats [35], reflecting the developmental changes in BMVEC TfR expression. Iron provided to hBMVEC in vitro as 59 Fe-Tf is accumulated in nearly five-fold excess to 59 Fe-citrate [36]. These data suggest that Tf-bound iron is the primary substrate for brain iron accumulation through postnatal ontogenesis when TfR expression in BMVEC is highest, and less so in adulthood when BMVEC TfR expression is low.…”

Section: Proteins Involved In Bmvec Iron Uptakementioning

confidence: 99%

“…neither did TfR [83]. Furthermore, recent data indicate that hBMVEC iron derived from TBI is exported from hBMVEC via a mechanism involving Fpn and an exocytoplasmic ferroxidase [36]. Removal of endogenous hBMVEC ferroxidase activity, an event which would not affect transcytosis, inhibits the efflux of Tf-iron from the cell, making the transcytosis model ever more unlikely [36].…”

Section: Proteins Involved In Bmvec Iron Uptakementioning

confidence: 99%

“…Beyond the duodenum, Fpn has been identified in several cell types in the CNS. These include BMVEC [14, 33, 36, 116, 117], neurons [116, 118, 119], oligodendrocytes [116, 118-120], astrocytes [47, 116], and the choroid plexus ependymal cells [116, 118]. Fpn transcript and protein have been localized to mouse BMVEC ensheathed by astrocytic endfeet [116].…”

Section: Proteins Involved In the Efflux Of Iron From Bmvecmentioning

confidence: 99%

See 1 more Smart Citation

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

McCarthy

Kosman

2014

Cell. Mol. Life Sci.

Self Cite

106

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There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease.

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“…Then, we focused on the upregulation of ferrous ion at long times of light exposure. Intracellular iron homeostasis is maintained by many regulatory mechanisms that tightly control iron uptake (Lane et al, 2013), storage (Tang et al, 2014, export (McCarthy and Kosman, 2013), and intracellular iron distribution (Christova and Templeton, 2007). Ferrous ion plays a pivotal role in regulating these factors through its interaction with iron response proteins (Goss and Theil, 2011).…”

Section: Discussionmentioning

confidence: 98%