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

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Abstract

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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Abbreviations

6-OHDA:

6-Hydroxydopamine

APP:

Amyloid-β precursor protein

sAPP:

Soluble β-secretase-cleaved APP

Aβ:

Amyloid-β

BBB:

Blood–brain barrier

BMVEC:

Brain microvascular endothelial cells

CNS:

Central nervous system

Cp:

Ceruloplasmin

CSF:

Cerebrospinal fluid

CTFβ:

β-Carboxyl-terminal fragment

Dcytb:

Duodenal cytochrome b

DMT1:

Divalent metal transporter 1

E°:

Electrochemical potential

Fpn:

Ferroportin

GPI:

Glycosylphosphatidylinositol-anchor

hBMVEC:

Human brain microvascular endothelial cell line

H-Ferritin:

Heavy chain ferritin

Hp:

Hephaestin

IRE:

Iron-responsive element

IRP:

Iron regulatory protein

L-Ferritin:

Light chain ferritin

P#:

Postnatal day #

sCp:

Soluble ceruloplasmin

SDR2:

Stromal cell-derived receptor 2

Steap:

Six transmembrane epithelial antigen of the prostate

Tf:

Transferrin

TfR:

Transferrin receptor

Zip8:

Zrt/Irt-like protein 8

Zip14:

Zrt/Irt-like protein 14

Zp:

Zyklopen

References

  1. Cheepsunthorn P, Palmer C, Connor JR (1998) Cellular distribution of ferritin subunits in postnatal rat brain. J Comp Neurol 400(1):73–86

    CAS  PubMed  Google Scholar 

  2. Todorich B et al (2009) Oligodendrocytes and myelination: the role of iron. Glia 57(5):467–478

    PubMed  Google Scholar 

  3. Salvador GA (2010) Iron in neuronal function and dysfunction. BioFactors 36(2):103–110

    CAS  PubMed  Google Scholar 

  4. Madsen E, Gitlin JD (2007) Copper and iron disorders of the brain. Annu Rev Neurosci 30(1):317–337

    CAS  PubMed  Google Scholar 

  5. Rivera-Mancía S et al (2010) The transition metals copper and iron in neurodegenerative diseases. Chem Biol Interact 186(2):184–199

    PubMed  Google Scholar 

  6. Salazar J et al (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci USA 105(47):18578–18583

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Rouault TA (2013) Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14(8):551–564

    CAS  PubMed  Google Scholar 

  8. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53

    CAS  PubMed  Google Scholar 

  9. Rouault TA, Cooperman S (2006) Brain iron metabolism. Semin Pediatr Neurol 13(3):142–148

    PubMed  Google Scholar 

  10. Xu J, Ling EA (1994) Studies of the ultrastructure and permeability of the blood–brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers. J Anat 184(Pt 2):227–237

    PubMed Central  PubMed  Google Scholar 

  11. Fisher J et al (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293(2):C641–C649

    CAS  PubMed  Google Scholar 

  12. Oide T et al (2006) Iron overload and antioxidative role of perivascular astrocytes in aceruloplasminemia. Neuropathol Appl Neurobiol 32(2):170–176

    CAS  PubMed  Google Scholar 

  13. Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5(5):347–360

    CAS  PubMed  Google Scholar 

  14. McCarthy RC, Kosman DJ (2014) Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells. PLoS ONE 9(2):e89003

    PubMed Central  PubMed  Google Scholar 

  15. Greco TM et al (2010) Quantitative mass spectrometry-based proteomics reveals the dynamic range of primary mouse astrocyte protein secretion. J Proteome Res 9(5):2764–2774

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Aisen P, Leibman A, Zweier J (1978) Stoichiometric and site characteristics of the binding of iron to human transferrin. J Biol Chem 253(6):1930–1937

    CAS  PubMed  Google Scholar 

  17. Byrne SL et al (2010) The unique kinetics of iron release from transferrin: the role of receptor, lobe–lobe interactions, and salt at endosomal pH. J Mol Biol 396(1):130–140

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Dhungana S et al (2004) Redox properties of human transferrin bound to its receptor. Biochemistry 43(1):205–209

    CAS  PubMed  Google Scholar 

  19. Weaver KD et al (2010) Role of citrate and phosphate anions in the mechanism of iron(III) sequestration by ferric binding protein: kinetic studies of the formation of the holoprotein of wild-type FbpA and its engineered mutants. Biochemistry 49(29):6021–6032

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Bloch B et al (1985) Transferrin gene expression visualized in oligodendrocytes of the rat brain by using in situ hybridization and immunohistochemistry. Proc Natl Acad Sci 82(19):6706–6710

    CAS  PubMed Central  PubMed  Google Scholar 

  21. De los Monteros AE et al (1990) Transferrin gene expression and secretion by rat brain cells in vitro. J Neurosci Res 25(4):576–580

    Google Scholar 

  22. Zahs KR, Bigornia V, Deschepper CF (1993) Characterization of “plasma proteins” secreted by cultured rat macroglial cells. Glia 7(2):121–133

    CAS  PubMed  Google Scholar 

  23. Connor JR, Fine RE (1986) The distribution of transferrin immunoreactivity in the rat central nervous system. Brain Res 368(2):319–328

    CAS  PubMed  Google Scholar 

  24. Koeller DM et al (1989) A cytosolic protein binds to structural elements within the iron regulatory region of the transferrin receptor mRNA. Proc Natl Acad Sci USA 86(10):3574–3578

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Casey JL et al (1988) Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science 240(4854):924–928

    CAS  PubMed  Google Scholar 

  26. Erlitzki R, Long JC, Theil EC (2002) Multiple, conserved iron-responsive elements in the 3′-untranslated region of transferrin receptor mRNA enhance binding of iron regulatory protein 2. J Biol Chem 277(45):42579–42587

    CAS  PubMed  Google Scholar 

  27. Mullner EW, Kuhn LC (1988) A region in the 3′ untranslated region mediates iron dependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell 53:815–825

    CAS  PubMed  Google Scholar 

  28. Raub TJ, Newton CR (1991) Recycling kinetics and transcytosis of transferrin in primary cultures of bovine brain microvessel endothelial cells. J Cell Physiol 149(1):141–151

    CAS  PubMed  Google Scholar 

  29. Burdo J et al (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 66(6):1198–1207

    CAS  PubMed  Google Scholar 

  30. Moos T, Morgan E (2000) Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol 20(1):77–95

    CAS  PubMed  Google Scholar 

  31. Moos T et al (2006) Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J Neurochem 98(6):1946–1958

    CAS  PubMed  Google Scholar 

  32. Rothenberger S et al (1996) Coincident expression and distribution of melanotransferrin and transferrin receptor in human brain capillary endothelium. Brain Res 712(1):117–121

    CAS  PubMed  Google Scholar 

  33. Yang W et al (2011) Transient expression of iron transport proteins in the capillary of the developing rat brain. Cell Mol Neurobiol 31(1):93–99

    CAS  PubMed  Google Scholar 

  34. Siddappa AJM et al (2002) Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci Res 68(6):761–775

    CAS  PubMed  Google Scholar 

  35. Taylor EM, Crowe A, Morgan EH (1991) Transferrin and iron uptake by the brain: effects of altered iron status. J Neurochem 57(5):1584–1592

    CAS  PubMed  Google Scholar 

  36. McCarthy RC, Kosman DJ (2013) Ferroportin and exocytoplasmic ferroxidase activity are required for brain microvascular endothelial cell iron efflux. J Biol Chem 288(24):17932–17940

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Ohgami RS et al (2005) Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 37(11):1264–1269

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Ohgami RS et al (2006) The Steap proteins are metalloreductases. Blood 108(4):1388–1394

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Knutson MD (2007) Steap proteins: implications for iron and copper metabolism. Nutr Rev 65(7):335–340

    PubMed  Google Scholar 

  40. McCarthy RC, Kosman DJ (2012) Mechanistic analysis of iron accumulation by endothelial cells of the BBB. Biometals 25(4):665–675

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Ohgami RS et al (2005) Nm1054: a spontaneous, recessive, hypochromic, microcytic anemia mutation in the mouse. Blood 106(10):3625–3631

    CAS  PubMed Central  PubMed  Google Scholar 

  42. McKie AT et al (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291(5509):1755–1759

    CAS  PubMed  Google Scholar 

  43. Wyman S et al (2008) Dcytb (Cybrd1) functions as both a ferric and a cupric reductase in vitro. FEBS Lett 582(13):1901–1906

    CAS  PubMed  Google Scholar 

  44. Latunde-Dada GO, Simpson RJ, McKie AT (2008) Duodenal cytochrome b expression stimulates iron uptake by human intestinal epithelial cells. J Nutr 138(6):991–995

    CAS  PubMed  Google Scholar 

  45. Turi JL et al (2006) Duodenal cytochrome b: a novel ferrireductase in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 291(2):L272–L280

    CAS  PubMed  Google Scholar 

  46. Tulpule K et al (2010) Uptake of ferrous iron by cultured rat astrocytes. J Neurosci Res 88(3):563–571

    CAS  PubMed  Google Scholar 

  47. Jeong SY, David S (2003) Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 278(29):27144–27148

    CAS  PubMed  Google Scholar 

  48. Loke SY et al (2013) Expression and localization of duodenal cytochrome b in the rat hippocampus after kainate-induced excitotoxicity. Neuroscience 245:179–190

    CAS  PubMed  Google Scholar 

  49. Lane DJ, Lawen A (2008) Non-transferrin iron reduction and uptake are regulated by transmembrane ascorbate cycling in K562 cells. J Biol Chem 283(19):12701–12708

    CAS  PubMed  Google Scholar 

  50. Lane DJ et al (2010) Two routes of iron accumulation in astrocytes: ascorbate-dependent ferrous iron uptake via the divalent metal transporter (DMT1) plus an independent route for ferric iron. Biochem J 432(1):123–132

    CAS  PubMed  Google Scholar 

  51. Oates PS et al (2000) Gene expression of divalent metal transporter 1 and transferrin receptor in duodenum of Belgrade rats. Am J Physiol Gastrointest Liver Physiol 278(6):G930–G936

    CAS  PubMed  Google Scholar 

  52. Fleming RE et al (1999) Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci USA 96(6):3143–3148

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Trinder D et al (2000) Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload. Gut 46(2):270–276

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Canonne-Hergaux F et al (2000) The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border. Blood 96(12):3964–3970

    CAS  PubMed  Google Scholar 

  55. Gunshin H et al (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388(6641):482–488

    CAS  PubMed  Google Scholar 

  56. Garrick MD et al (2006) DMT1: which metals does it transport? Biol Res 39:79–85

    CAS  PubMed  Google Scholar 

  57. Knöpfel M, Smith C, Solioz M (2005) ATP-driven copper transport across the intestinal brush border membrane. Biochem Biophys Res Commun 330(3):645–652

    PubMed  Google Scholar 

  58. Garrick MD, Kuo HC, Vargas F, Singleton S, Zhao L, Smith JJ, Paradkar P, Roth JA, Garrick LM (2006) Comparison of mammalian cell lines expressing distinct isoforms of divalent metal transporter 1 in a tetracycline-regulated fashion. Biochem J 398(3):539–545

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Worthington MT et al (2000) Functional properties of transfected human DMT1 iron transporter. Am J Physiol Gastrointest Liver Physiol 279(6):G1265–G1273

    CAS  PubMed  Google Scholar 

  60. McEwan GTA et al (1988) The effect of Escherichia coli STa enterotoxin and other secretagogues on mucosal surface pH of rat small intestine. Proc R Soc Lond B Biol Sci 234(1275):219–237

    CAS  PubMed  Google Scholar 

  61. Quigley EM, Turnberg LA (1992) Studies of luminal and mucosal pH in reflux esophagitis and antral gastritis. Dig Dis 10(3):134–143

    CAS  PubMed  Google Scholar 

  62. Conrad ME et al (2000) Separate pathways for cellular uptake of ferric and ferrous iron. Am J Physiol Gastrointest Liver Physiol 279(4):G767–G774

    CAS  PubMed  Google Scholar 

  63. Mackenzie B et al (2006) Divalent metal-ion transporter DMT1 mediates both H+-coupled Fe2+ transport and uncoupled fluxes. Pflügers Arch 451(4):544–558

    CAS  PubMed  Google Scholar 

  64. Skjørringe T, Møller LB, Moos T (2012) Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders. Front Pharmacol 3:169

    PubMed Central  PubMed  Google Scholar 

  65. Fleming MD et al (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95(3):1148–1153

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Farcich EA, Morgan EH (1992) Diminished iron acquisition by cells and tissues of Belgrade laboratory rats. Am J Physiol 262(2):R220–R224

    CAS  PubMed  Google Scholar 

  67. Burdo JR et al (1999) Cellular distribution of iron in the brain of the Belgrade rat. Neuroscience 93(3):1189–1196

    CAS  PubMed  Google Scholar 

  68. Taylor KM et al (2005) Structure–function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Lett 579(2):427–432

    CAS  PubMed  Google Scholar 

  69. Liuzzi JP et al (2006) Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci USA 103(37):13612–13617

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Pinilla-Tenas JJ et al (2011) Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol Cell Physiol 301(4):C862–C871

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Zhao N et al (2010) ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J Biol Chem 285(42):32141–32150

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Girijashanker K et al (2008) Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol Pharm 73(5):1413–1423

    CAS  Google Scholar 

  73. Wang C-Y et al (2012) ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem 287(41):34032–34043

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Kraiter DC et al (1998) A determination of the reduction potentials for diferric and C- and N-lobe monoferric transferrins at endosomal pH (5.8). Inorg Chem 37(5):964–968

    CAS  Google Scholar 

  75. Dhungana S et al (2003) Redox properties of human transferrin bound to its receptor†. Biochemistry 43(1):205–209

    Google Scholar 

  76. Byrne S, Mason A (2009) Human serum transferrin: a tale of two lobes. Urea gel and steady state fluorescence analysis of recombinant transferrins as a function of pH, time, and the soluble portion of the transferrin receptor. J Biol Inorg Chem 14(5):771–781

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Nelson N, Harvey WR (1999) Vacuolar and plasma membrane proton-adenosinetriphosphatases. Physiol Rev 79(2):361–385

    CAS  PubMed  Google Scholar 

  78. Moos T et al (2007) Iron trafficking inside the brain. J Neurochem 103(5):1730–1740

    CAS  PubMed  Google Scholar 

  79. Descamps L et al (1996) Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells. Am J Physiol 270(4):H1149–H1158

    CAS  PubMed  Google Scholar 

  80. Kintner DB et al (2000) 31P-MRS-based determination of brain intracellular and interstitial pH: its application to in vivo H+ compartmentation and cellular regulation during hypoxic/ischemic conditions. Neurochem Res 25(9):1385–1396

    CAS  PubMed  Google Scholar 

  81. Bradbury MWB (1997) Transport of iron in the blood–brain–cerebrospinal fluid system. J Neurochem 69(2):443–454

    CAS  PubMed  Google Scholar 

  82. Crowe A, Morgan EH (1992) Iron and transferrrin uptake by brain and cerebrospinal fluid in the rat. Brain Res 592(1–2):8–16

    CAS  PubMed  Google Scholar 

  83. Manich G et al (2013) Study of the transcytosis of an anti-transferrin receptor antibody with a Fab′ cargo across the blood–brain barrier in mice. Eur J Pharm Sci. 49:556–564

    CAS  PubMed  Google Scholar 

  84. Laurie GW, Leblond CP, Martin GR (1982) Localization of type IV collagen, laminin, heparan sulfate proteoglycan, and fibronectin to the basal lamina of basement membranes. J Cell Biol 95(1):340–344

    CAS  PubMed  Google Scholar 

  85. Meguro R et al (2008) 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. Arch Histol Cytol 71(4):205–222

    CAS  PubMed  Google Scholar 

  86. Riemer J et al (2004) Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells. Anal Biochem 331(2):370–375

    CAS  PubMed  Google Scholar 

  87. Wolcott GH, Boyer PD (1948) A colorimetric method for the determination of citric acid in blood and plasma. J Biol Chem 172(2):729–736

    CAS  PubMed  Google Scholar 

  88. Bates GW, Billups C, Saltman P (1967) The kinetics and mechanism of iron(III) exchange between chelates and transferrin. J Biol Chem 242(12):2810–2815

    CAS  PubMed  Google Scholar 

  89. Königsberger L-C et al (2000) Complexation of iron(III) and iron(II) by citrate. Implications for iron speciation in blood plasma. J Inorg Biochem 78(3):175–184

    PubMed  Google Scholar 

  90. Hearers AF (1971) Citrate and alpha-ketoglutarate in cerebrospinal fluid and blood. Neurology 21(10):1059

    Google Scholar 

  91. Donovan A et al (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403(6771):776–781

    CAS  PubMed  Google Scholar 

  92. McKie AT et al (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5(2):299–309

    CAS  PubMed  Google Scholar 

  93. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275(26):19906–19912

    CAS  PubMed  Google Scholar 

  94. Mitchell CJ et al (2014) Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc. Am J Physiol Cell Physiol 306(5):C450–C459

    CAS  PubMed  Google Scholar 

  95. Madejczyk MS, Ballatori N (2012) The iron transporter ferroportin can also function as a manganese exporter. Biochim Biophys Acta 1818(3):651–657

    CAS  PubMed  Google Scholar 

  96. Yin Z et al (2010) Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation. J Neurochem 112(5):1190–1198

    CAS  PubMed Central  PubMed  Google Scholar 

  97. De Domenico I et al (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J 26(12):2823–2831

    PubMed Central  PubMed  Google Scholar 

  98. De Domenico I et al (2007) Evidence for the multimeric structure of ferroportin. Blood 109(5):2205–2209

    PubMed Central  PubMed  Google Scholar 

  99. De Domenico I et al (2005) The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci USA 102(25):8955–8960

    PubMed Central  PubMed  Google Scholar 

  100. De Domenico I et al (2010) Human mutation D157G in ferroportin leads to hepcidin-independent binding of Jak2 and ferroportin down-regulation. Blood 115(14):2956–2959

    PubMed Central  PubMed  Google Scholar 

  101. Montosi G et al (2001) Autosomal-dominant hemochrom-atosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108(4):619–623

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Liu X-B, Yang F, Haile DJ (2005) Functional consequences of ferroportin 1 mutations. Blood Cells Mol Dis 35(1):33–46

    CAS  PubMed  Google Scholar 

  103. Wallace DF, Harris JM, Subramaniam VN (2010) Functional analysis and theoretical modeling of ferroportin reveals clustering of mutations according to phenotype. Am J Physiol Cell Physiol 298(1):C75–C84

    CAS  PubMed  Google Scholar 

  104. Leipuviene R, Theil E (2007) The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen. Cell Mol Life Sci 64(22):2945–2955

    CAS  PubMed  Google Scholar 

  105. Ward DM, Kaplan J (2012) Ferroportin-mediated iron transport: expression and regulation. Biochim Biophys Acta 1823(9):1426–1433

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Zhang D-L et al (2011) Hepcidin regulates ferroportin expression and intracellular iron homeostasis of erythroblasts. Blood 118(10):2868–2877

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Nemeth E et al (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704):2090–2093

    CAS  PubMed  Google Scholar 

  108. Qiao B et al (2012) Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab 15(6):918–924

    CAS  PubMed Central  PubMed  Google Scholar 

  109. De Domenico I et al (2008) The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab 8(2):146–156

    PubMed Central  PubMed  Google Scholar 

  110. De Domenico I et al (2007) The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 18(7):2569–2578

    PubMed Central  PubMed  Google Scholar 

  111. Ross Sandra L et al (2012) Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT. Cell Metab 15(6):905–917

    CAS  PubMed  Google Scholar 

  112. Preza GC et al (2013) Cellular catabolism of the iron-regulatory peptide hormone hepcidin. PLoS ONE 8(3):e58934

    PubMed Central  PubMed  Google Scholar 

  113. Kono S et al (2010) Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin. Biochim Biophys Acta 1802(11):968–975

    CAS  PubMed  Google Scholar 

  114. Zechel S, Huber-Wittmer K, von Bohlen O, Halbach (2006) Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J Neurosci Res 84(4):790–800

  115. Han O, Kim E-Y (2007) Colocalization of ferroportin-1 with hephaestin on the basolateral membrane of human intestinal absorptive cells. J Cell Biochem 101(4):1000–1010

    CAS  PubMed  Google Scholar 

  116. Wu LJ-c et al (2004) Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier. Brain Res 1001(1–2):108–117

    CAS  PubMed  Google Scholar 

  117. Raha A et al (2013) The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease. Acta Neuro Comms 1(1):55

    Google Scholar 

  118. Boserup M et al (2011) Heterogenous distribution of ferroportin-containing neurons in mouse brain. Biometals 24(2):357–375

    CAS  PubMed  Google Scholar 

  119. Moos T, Rosengren Nielsen T (2006) Ferroportin in the postnatal rat brain: implications for axonal transport and neuronal export of iron. Semin Pediatr Neurol 13(3):149–157

    PubMed  Google Scholar 

  120. Schulz K et al (2011) Iron efflux from oligodendrocytes is differentially regulated in gray and white matter. J Neurosci 31(37):13301–13311

    CAS  PubMed  Google Scholar 

  121. Enerson BE, Drewes LR (2005) The rat blood–brain barrier transcriptome. J Cereb Blood Flow Metab 26(7):959–973

    PubMed  Google Scholar 

  122. Fung E et al (2013) High-throughput screening of small molecules identifies hepcidin antagonists. Mol Pharm 83(3):681–690

    CAS  Google Scholar 

  123. Nittis T, Gitlin JD (2004) Role of copper in the proteosome-mediated degradation of the multicopper oxidase hephaestin. J Biol Chem 279(24):25696–25702

    CAS  PubMed  Google Scholar 

  124. Griffiths TAM, Mauk AG, MacGillivray RTA (2005) Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity. Biochemistry 44(45):14725–14731

    CAS  PubMed  Google Scholar 

  125. Bento I et al (2007) Ceruloplasmin revisited: structural and functional roles of various metal cation-binding sites. Acta Crystallogr D Biol Crystallogr 63(2):240–248

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Sato M, Gitlin JD (1991) Mechanisms of copper incorporation during the biosynthesis of human ceruloplasmin. J Biol Chem 266(8):5128–5134

    CAS  PubMed  Google Scholar 

  127. Zaitseva I et al (1996) The X-ray structure of human serum ceruloplasmin at 3.1 Å: nature of the copper centres. J Biol Inorg Chem 1(1):15–23

    CAS  Google Scholar 

  128. Chen H et al (2010) Identification of zyklopen, a new member of the vertebrate multicopper ferroxidase family, and characterization in rodents and human cells. J Nutr 140(10):1728–1735

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Danzeisen R et al (2000) The effect of ceruloplasmin on iron release from placental (BeWo) cells; evidence for an endogenous Cu oxidase. Placenta 21(8):805–812

    CAS  PubMed  Google Scholar 

  130. Danzeisen R et al (2002) Placental ceruloplasmin homolog is regulated by iron and copper and is implicated in iron metabolism. Am J Physiol Cell Physiol 282(3):C472–C478

    CAS  PubMed  Google Scholar 

  131. Vulpe CD et al (1999) Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21(2):195–199

    CAS  PubMed  Google Scholar 

  132. Lee S-M et al (2012) Iron repletion relocalizes hephaestin to a proximal basolateral compartment in polarized MDCK and Caco2 cells. Biochem Biophys Res Commun 421(3):449–455

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Qian Z-M et al (2007) Development and iron-dependent expression of hephaestin in different brain regions of rats. J Cell Biochem 102(5):1225–1233

    CAS  PubMed  Google Scholar 

  134. Wang J, Jiang H, Xie J-X (2007) Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. Eur J Neurosci 25(9):2766–2772

    PubMed  Google Scholar 

  135. Cui R et al (2009) Age-dependent expression of hephaestin in the brain of ceruloplasmin-deficient mice. J Trace Elem Med Biol 23(4):290–299

    CAS  PubMed  Google Scholar 

  136. Gitlin JD (1998) Aceruloplasminemia. Pediatr Res 44(3):271–276

    CAS  PubMed  Google Scholar 

  137. Klomp LW et al (1996) Ceruloplasmin gene expression in the murine central nervous system. J Clin Invest 98(1):207–215

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Chang YZ et al (2005) Effects of development and iron status on ceruloplasmin expression in rat brain. J Cell Physiol 204(2):623–631

    CAS  PubMed  Google Scholar 

  139. Klomp LWJ, Gitlin JD (1996) Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum Mol Genet 5(12):1989–1996

    CAS  PubMed  Google Scholar 

  140. Patel BN, David S (1997) A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes. J Biol Chem 272(32):20185–20190

    CAS  PubMed  Google Scholar 

  141. Patel BN, Dunn RJ, David S (2000) Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. J Biol Chem 275(6):4305–4310

    CAS  PubMed  Google Scholar 

  142. Mukhopadhyay CK, Attieh ZK, Fox PL (1998) Role of ceruloplasmin in cellular iron uptake. Science 279(5351):714–717

    CAS  PubMed  Google Scholar 

  143. Attieh ZK et al (1999) Ceruloplasmin ferroxidase activity stimulates cellular iron uptake by a trivalent cation-specific transport mechanism. J Biol Chem 274(2):1116–1123

    CAS  PubMed  Google Scholar 

  144. Gaasch J et al (2007) Brain iron toxicity: differential responses of astrocytes, neurons, and endothelial cells. Neurochem Res 32(7):1196–1208

    CAS  PubMed  Google Scholar 

  145. Marksteiner J, Humpel C (2007) Beta-amyloid expression, release and extracellular deposition in aged rat brain slices. Mol Psychiatry 13(10):939–952

    PubMed  Google Scholar 

  146. Siman R et al (1989) Expression of 2-amyloid precursor protein in reactive astrocytes following neuronal damage. Neuron 3(3):275–285

    CAS  PubMed  Google Scholar 

  147. Ford GC et al (1984) Ferritin: design and formation of an iron-storage molecule. Philos Trans R Soc Lond B Biol Sci 304(1121):551–565

    CAS  PubMed  Google Scholar 

  148. Theil EC (1987) Ferritin: structure, gene regulation, and cellular function in animals, plants, and microorganisms. Annu Rev Biochem 56(1):289–315

    CAS  PubMed  Google Scholar 

  149. Aisen P, Listowsky I (1980) Iron transport and storage proteins. Annu Rev Biochem 49(1):357–393

    CAS  PubMed  Google Scholar 

  150. Arosio P, Adelman TG, Drysdale JW (1978) On ferritin heterogeneity. Further evidence for heteropolymers. J Biol Chem 253(12):4451–4458

    CAS  PubMed  Google Scholar 

  151. Miller LL et al (1991) Iron-independent induction of ferritin H chain by tumor necrosis factor. Proc Natl Acad Sci 88(11):4946–4950

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Lawson DM et al (1989) Identification of the ferroxidase centre in ferritin. FEBS Lett 254(1–2):207–210

    CAS  PubMed  Google Scholar 

  153. Levi S et al (1992) Evidence of H- and L-chains have co-operative roles in the iron-uptake mechanism of human ferritin. Biochem J 288(2):591–596

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Rouault T, Zhang D-L, Jeong S (2009) Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins. Metab Brain Dis 24(4):673–684

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Li Z, Chen-Roetling J, Regan RF (2009) Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity. Free Radic Res 43(6):613–621

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Todorich B, Zhang X, Connor JR (2011) H-ferritin is the major source of iron for oligodendrocytes. Glia 59(6):927–935

    PubMed  Google Scholar 

  157. Jacobson S (1963) Sequence of myelinization in the brain of the albino rat. A. Cerebral cortex, thalamus and related structures. J Comp Neurol 121(1):5–29

    CAS  PubMed  Google Scholar 

  158. Kitazume S et al (2010) Brain endothelial cells produce amyloid β from amyloid precursor protein 770 and preferentially secrete the o-glycosylated form. J Biol Chem 285(51):40097–40103

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Duce JA et al (2010) Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 142(6):857–867

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Ebrahimi KH, Hagedoorn P-L, Hagen WR (2012) A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron. PLoS ONE 7(8):e40287

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Honarmand Ebrahimi K et al (2013) The amyloid precursor protein (APP) does not have a ferroxidase site in its E2 domain. PLoS ONE 8(8):72177

    Google Scholar 

  162. McCarthy RC, Park YH, Kosman DJ (2014) sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep 15(7):809–815

    CAS  PubMed  Google Scholar 

  163. Rogers JT et al (2008) Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer’s disease. Biochem Soc Trans 36(Pt 6):1282–1287

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Cho HH et al (2010) Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1. J Biol Chem 285(41):31217–31232

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Moos T (1995) Developmental profile of non-heme iron distribution in the rat brain during ontogenesis. Dev Brain Res 87(2):203–213

    CAS  Google Scholar 

  166. Hadziahmetovic M et al (2011) Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice. Invest Ophthalmol Vis Sci 52(1):109–118

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Wang SM et al (2010) Role of hepcidin in murine brain iron metabolism. Cell Mol Life Sci 67(1):123–133

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Pellerin L, Magistretti PJ (2003) Food for thought: challenging the dogmas. J Cereb Blood Flow Metab 23:1282–1286

    PubMed  Google Scholar 

  169. Newman EA (2003) New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci 26(10):536–542

    CAS  PubMed  Google Scholar 

  170. Pelizzoni I et al (2013) Iron uptake in quiescent and inflammation-activated astrocytes: a potentially neuroprotective control of iron burden. Biochim Biophys Acta 1832(8):1326–1333

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Zonta M et al (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50

    CAS  PubMed  Google Scholar 

  172. Harris ZL et al (1995) Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci USA 92(7):2539–2543

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Yoshida K et al (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9(3):267–272

    CAS  PubMed  Google Scholar 

  174. Kaneko K et al (2002) Astrocytic deformity and globular structures are characteristic of the brains of patients with aceruloplasminemia. J Neuropathol Exp Neurol 61(12):1069–1077

    PubMed  Google Scholar 

  175. Langer F et al (2011) Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J Neurosci 31(41):14488–14495

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Tabaton M, Tamagno E (2007) The molecular link between β- and γ-secretase activity on the amyloid β precursor protein. Cell Mol Life Sci 64(17):2211–2218

    CAS  PubMed  Google Scholar 

  177. Cai H et al (2001) BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci 4:233–234

    CAS  PubMed  Google Scholar 

  178. Zheng H, Koo E (2006) The amyloid precursor protein: beyond amyloid. Mol Neurodegener 1(1):5

    PubMed Central  PubMed  Google Scholar 

  179. Bolognin S et al (2011) Aluminum, copper, iron and zinc differentially alter amyloid-Aβ1–42 aggregation and toxicity. Int J Biochem Cell Biol 43(6):877–885

    CAS  PubMed  Google Scholar 

  180. Kayed R et al (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2(1):18

    PubMed Central  PubMed  Google Scholar 

  181. Broersen K, Rousseau F, Schymkowitz J (2010) The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer’s disease: oligomer size or conformation? Alzheimers Res Ther 2(4):12

    PubMed Central  PubMed  Google Scholar 

  182. Everett J et al (2014) Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer’s disease peptide β-amyloid (1–42). J R Soc Interface 11(95)

  183. Rottkamp CA et al (2001) Redox-active iron mediates amyloid-β toxicity. Free Radic Biol Med 30(4):447–450

    CAS  PubMed  Google Scholar 

  184. Guo C et al (2012) Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 34:562–575

    PubMed  Google Scholar 

  185. Guo C et al (2013) Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int 62(2):165–172

    CAS  PubMed  Google Scholar 

  186. Aldred AR et al (1987) Distribution of transferrin synthesis in brain and other tissues in the rat. J Biol Chem 262(11):5293–5297

    CAS  PubMed  Google Scholar 

  187. Giometto B et al (1990) Transferrin receptors in rat central nervous system: an immunocytochemical study. J Neurol Sci 98(1):81–90

    CAS  PubMed  Google Scholar 

  188. Du F et al (2011) Hepcidin directly inhibits transferrin receptor 1 expression in astrocytes via a cyclic AMP-protein kinase a pathway. Glia 59(6):936–945

    PubMed  Google Scholar 

  189. Espinosa de los Monteros A, Foucaud B (1987) Effect of iron and transferrin on pure oligodendrocytes in culture; characterization of a high-affinity transferrin receptor at different ages. Dev Brain Res 35(1):123–130

    CAS  Google Scholar 

  190. Moos T (1995) Increased accumulation of transferrin by motor neurons of the mouse mutant progressive motor neuronopathy (pmn/pmn). J Neurocytol 24(5):389–398

    CAS  PubMed  Google Scholar 

  191. Moos T (1995) Age-dependent uptake and retrograde axonal transport of exogenous albumin and transferrin in rat motor neurons. Brain Res 672(1–2):14–23

    CAS  PubMed  Google Scholar 

  192. He L et al (2006) ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol Pharm 70(1):171–180

    CAS  Google Scholar 

  193. Iyengar V, Pullakhandam R, Nair KM (2009) Iron-zinc interaction during uptake in human intestinal Caco-2 cell line: Kinetic analyses and possible mechanism. Indian J Biochem Biophys 46:8

    Google Scholar 

  194. Liu Z et al (2008) Cd2+ versus Zn2+ uptake by the ZIP8-dependent symporter: kinetics, electrogenicity and trafficking. Biochem Biophys Res Commun 365(4):814–820

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22(23):3099–3108

    CAS  PubMed  Google Scholar 

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  1. Department of Biochemistry, University at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, 14214, USA

    Ryan C. McCarthy & Daniel J. Kosman

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McCarthy, R.C., Kosman, D.J. Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy. Cell. Mol. Life Sci. 72, 709–727 (2015). https://doi.org/10.1007/s00018-014-1771-4

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