Brain iron transport

Abstract

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.

Overdosing on iron: Elevated iron and degenerative brain disorders

“…enters the brain interstitium through the epithelial cell lining of the choroid plexus, which has a more permeable than the lining of the BBB. 55,56 The choroid plexus expresses the major components for iron transport including high levels of both Tfr11and DMT1 as well as FPN1, DcytB, STEAP3 and FPN1 and, as described above, ceruloplasmin. 57,58 Iron transport within the brain Much of the iron released from endothelial cells of the BBB is taken up by the end-feet of astrocytes and then made available to neurons and other cells types via release in the brain parenchyma 59,60 (Figure 3).…”

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

“…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).…”

“…Neurons and microglia can acquire iron by means of the Tf/TfR1 pathway or absorb non-Tf-bound iron (NTBI) via the luminal DMT1-dependent pathway (Ke and Ming Qian, 2003;Urrutia et al, 2013;Zarruk et al, 2015). Recent studies show that the binding of H-ferritin to the H-ferritin receptor (Tim-1/2) may be the major source of iron uptaking for oligodendrocytes (Todorich et al, 2011;Chiou et al, 2018;Qian and Ke, 2019). In addition to the Tf/TfR1 or DMT1 pathway, astrocytes may acquire iron by their end-feet processes (Biasiotto et al, 2016;Qian and Ke, 2019;Xu et al, 2019).…”

“…Recent studies show that the binding of H-ferritin to the H-ferritin receptor (Tim-1/2) may be the major source of iron uptaking for oligodendrocytes (Todorich et al, 2011;Chiou et al, 2018;Qian and Ke, 2019). In addition to the Tf/TfR1 or DMT1 pathway, astrocytes may acquire iron by their end-feet processes (Biasiotto et al, 2016;Qian and Ke, 2019;Xu et al, 2019). In this way, brain iron levels are precisely regulated to participate in normal neuronal function.…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…In addition to NTBI uptake via a Tf‐independent mechanism, microglia may also be able to take up Tf‐Fe via a TfR1/DMT1 pathway. Iron efflux from the neuron is mediated by ferroportin 1/ceruloplasmin (Fpn1/CP) and/or Fpn1/hephaestin (Heph) pathways, from astrocytes by Fpn1/CP, and from oligodendrocytes and microglia by the Fpn1/Heph route . Iron is constantly transported into the brain, it must also be exported from the brain to maintain brain iron homeostasis.…”