Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases

Abstract

Iron (Fe) and copper (Cu) are essential to neuronal function; excess or deficiency of either is known to underlie the pathoetiology of several commonly known neurodegenerative disorders. This delicate balance of Fe and Cu in the central milieu is maintained by the brain barrier systems, i.e., the blood-brain barrier (BBB) between the blood and brain interstitial fluid and the blood-cerebrospinal fluid barrier (BCB) between the blood and cerebrospinal fluid (CSF). This review provides a concise description on the structural and functional characteristics of the brain barrier systems. Current understanding of Fe and Cu transport across the brain barriers is thoroughly examined, with major focuses on whether the BBB and BCB coordinate the direction of Fe and Cu fluxes between the blood and brain/CSF. In particular, the mechanism by which pertinent metal transporters in the barriers, such as the transferrin receptor (TfR), divalent metal transporter (DMT1), copper transporter (CTR1), ATP7A/B, and ferroportin (FPN), regulate metal movement across the barriers is explored. Finally, the detrimental consequences of dysfunctional metal transport by brain barriers, as a result of endogenous disorders or exogenous insults, are discussed. Understanding the regulation of Fe and Cu homeostasis in the central nervous system aids in the design of new drugs targeted on the regulatory proteins at the brain barriers for the treatment of metal's deficiency or overload-related neurological diseases.

Fig. 1

Brain Fluid Compartments and Brain Barrier Systems. Substances in the blood can pass across the blood-brain barrier (BBB) to enter the brain interstitial fluid (ISF) and come into contact with neuronal structures. Substances in the blood can also pass across the blood-CSF barrier (BCB) to enter the cerebrospinal fluid (CSF). Since there is no structural barrier between the CSF and ISF, materials in these two fluid compartment can freely exchange. The intra-cerebroventricular (ICV) injection of toxic chemicals produces more severe neurotoxicity than do other routes of exposure, suggesting a direct delivery of chemicals from the CSF to the ISF. Metals such as Fe and Cu may enter the ISF via the BBB and be transported back into the blood via the efflux mechanism at the BCB.

Fig. 2

Iron Regulatory Protein-1 (IRP1) and Intracellular Fe Regulation. mRNAs encoding transferrin receptor (TfR) and divalent metal transporter (DMT1) possess the stem-loop structure called the iron responsive element (IRE) at the 3′ untranslated region. In the Fe deficient state, the conformation change in the [4Fe-4S] active center in IRP1 allows the IPR1 to bind to the stem loops of TfR or DMT1 mRNAs; the binding stabilizes the translation, produces more TfR or DMT1, and allows the cell to take up more Fe to meet the metabolic needs.

Fig. 3

Iron Transport by the BBB and BCB. Most Fe molecules in the blood are bound to Tf. At the BBB, Fe-Tf is transported into the cerebral endothelial cells by TfR; a portion of free Fe ions are transported via DMT1 or other yet-identified transporters. The FPN exports Fe into the interstitial fluid, where Fe is utilized by cells. Excess Fe ions in the CSF are taken up by DMT1 in choroidal epithelial microvilli and transported back to the blood.

Fig. 4

Intracellular Distribution of CTR1 and ATP7A in Choroid Plexus by Confocal Microscopy. (A). Presence of CTR1 in rat choroid plexus. CTR1 signals are cytosol-distributed mainly between the nuclei and apical side membrane. The arrow indicates the apical microvilli without CTR1 staining. (B). Subchronic exposure to Mn in rats causes the relocation of CTR1 to the apical brush board of choroidal epithelium. The arrow indicates a substantial staining in the apical microvilli. (C). Presence of ATP7A in rat choroid plexus. ATP7A signals are evenly distributed in the cytosol. The arrow indicates red blood cells in choroidal capillary vessel. Left: immunohistochemical staining; Middle: transmission image; Right: imaging overlay.

Fig. 5

Cu Transport by the BBB and BCB. Most of the Cu molecules in the blood are bound to ceruloplasmin (Cp). At the BBB, free Cu is transported into the cerebral endothelial cells by CTR1; a portion of free Cu ions are transported via DMT1 or other yet-identified transporters. ATOX1 delivers Cu to either ATP7A or ATP7B to be released into the interstitial fluid, where Cu is utilized by neurons and neuroglial cells. Excess Cu ions in the CSF are taken up by CTR1 or DMT1 in choroidal epithelial microvilli and transported back to the blood.