Abstract
The transcellular trafficking of iron from the blood into the brain interstitium depends on iron uptake proteins in the apical membrane of brain microvascular capillary endothelial cells and efflux proteins at the basolateral, abluminal membrane. In this review, we discuss the three mechanisms by which these cells take-up iron from the blood and the sole mechanism by which they efflux this iron into the abluminal space. We then focus on the regulation of this efflux pathway by exocrine factors that are released from neighboring astrocytes. Also discussed are the cytokines secreted by capillary cells that regulate the expression of these glial cell signals. Among the interstitial factors that regulate iron efflux into the brain is the Amyloid precursor protein (APP). The role of this amyliodogenic species in brain iron metabolism is discussed. Last, we speculate on the potential relationship between iron transport at the blood-brain barrier and neurological disorders associated with iron mismanagement.
Highlights
Organismal iron is a co-factor utilized for several specific enzymatic processes and, in higher eukaryotes, iron is essential for hemoglobin, myoglobin, neurotransmitter synthesis, myelination of neurons, and energy-producing redox reactions (Beard, 2003; Levi and Rovida, 2009; Todorich et al, 2009; Horowitz and Greenamyre, 2010; Chen and Paw, 2012)
Addition of hepcidin to cultured primary brain microvascular endothelial cells (BMVEC) reduces the expression of Fpn and Tf receptor (TfR) and divalent metal transporter 1 (DMT1) suggesting that TfR and DMT1 transcripts are responding to elevated iron within the cell caused by Fpn depletion
In 2014, we demonstrated that hepcidin, secreted from astrocytes, induced the internalization and ubiquitination of human BMVEC (hBMVEC) Fpn when seeded in close proximity in a model blood-brain barrier (BBB) system (McCarthy and Kosman, 2014b)
Summary
Organismal iron is a co-factor utilized for several specific enzymatic processes and, in higher eukaryotes, iron is essential for hemoglobin, myoglobin, neurotransmitter synthesis, myelination of neurons, and energy-producing redox reactions (Beard, 2003; Levi and Rovida, 2009; Todorich et al, 2009; Horowitz and Greenamyre, 2010; Chen and Paw, 2012). The brain, which is the most metabolically active organ in the body, has a high demand for iron and actively engages in maintaining appropriate amounts of the element within its confines. Brain iron maintenance is complex and involves both diurnal and regional regulation (Unger et al, 2009, 2014). The brain utilizes a detailed regulatory network involving cell-to-cell signaling and acute phase ironregulatory proteins to transport iron from the blood, across the blood-brain barrier (BBB), and into the brain. Before iron can enter the brain through the BBB it must first be acquired from the diet through a separate barrier system: the duodenal enterocyte barrier.
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