Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1

Abstract

Rats were studied for [ 59 I]transferrin uptake in total brain, and fractions containing brain capillary endothelial cells (BCECs) or neurons and glia. 59 Fe was transported through Throughout life, brain capillary endothelial cells (BCECs) transport iron from blood plasma to the brain interior via transferrin receptor-mediated uptake at their luminal side. This iron uptake ensures an adequate iron supply to neuronal and glial cells, which require iron for mitochondrial respiration, neurotransmitter synthesis and myelin formation. The blood-to-brain iron transport is regulated via BCEC transferrin receptor expression, which yields higher iron uptake during development and conditions with inadequate iron supply (Taylor et al. 1991). Conversely, BCECs downregulate this transport when sufficient neuronal and glial iron prevails, thus preventing iron overload in the brain (Crowe and Morgan 1992). This is also reflected by the absence of significant cellular damage in the brain as opposed to virtually any other organ in the body during systemic iron overload . Low molecular weight iron complexes of non-transferrinbound iron (NTBI) are absent from blood plasma under physiological conditions ( Abbreviations used: Alb, albumin, AUC, area under the plasma radioactivity curve; b/b, homozygous Belgrade rat; BCEC, brain capillary endothelial cell; DAB, diaminobenzidine; DMT1, divalent metal transporter 1; IRE, iron-responsive element; KPBS, potassium phosphate-buffered saline; NTBI, non-transferrin bound iron; +/b, heterozygous Belgrade rat; P, postnatal; PBS, phosphate-buffered saline; PFA, paraformaldehyde; TCA, trichloroacetic acid; Trf, transferrin; V D , volume of distribution.

Cellular and subcellular localizations of nonheme ferric and ferrous iron in the rat brain: a light and electron microscopic study by the perfusion-Perls and -Turnbull methods

“…Astrocytes, considered to be important regulators for iron import into the brain (Moos et al, 2006), have iron transporters such as ferroportin for iron excretion into the interstitial fluid (Zoller et al, 2002;Dringen et al, 2007). We observed pericapillary astrocytes containing nonheme Fe(III) and Fe(II) in lysosomes and the cytosol.…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…However, other studies failed to show DMT1 expression in brain capillary endothelial cells [131,132]. Moreover, vascular sites of putative DMT1-CTR1 co-expression, as the blood-brain barrier, show a predominant presence of CTR1 high-affinity importer [131,133]. So, in the absence of direct evidence, it is plausible that DMT1 plays a marginal role in vascular copper management.…”

“…The protein expression has been detected in rat brain microvascular endothelial cells [114,128,129] and HUVECs [130]. However, other studies failed to show DMT1 expression in brain capillary endothelial cells [131,132]. Moreover, vascular sites of putative DMT1-CTR1 co-expression, as the blood-brain barrier, show a predominant presence of CTR1 high-affinity importer [131,133].…”

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

“…We previously reported the presence of DMT1 in ECs of the BBB both in rats 26 and humans. 8 Although there is not universal agreement on this point, 27 the requirement for a mechanism for iron to enter the EC labile iron 59 Fe-NTA was added to the endothelial cell monolayer in the upper chamber and incubated overnight. The medium from upper and lower chambers was removed and fresh media were returned to the upper chamber and artificial CSF or CSF from either ID or iron-sufficient (IS) monkeys was added to the basal chamber.…”