Advertisement

European Biophysics Journal

, Volume 37, Issue 3, pp 295–300 | Cite as

Copper transport and Alzheimer’s disease

  • Ian G. Macreadie
Review

Abstract

This brief review discusses copper transport in humans, with an emphasis on knowledge learned from one of the simplest model organisms, yeast. There is a further focus on copper transport in Alzheimer’s Disease (AD). Copper homeostasis is essential for the well-being of all organisms, from bacteria to yeast to humans: survival depends on maintaining the required supply of copper for the many enzymes, dependent on copper for activity, while ensuring that there is no excess free copper, which would cause toxicity. A virtual orchestra of proteins are required to achieve copper homeostasis. For copper uptake, Cu(II) is first reduced to Cu(I) via a membrane-bound reductase. The reduced copper can then be internalised by a copper transporter where it is transferred to copper chaperones for transport and specific delivery to various organelles. Of significance are internal copper transporters, ATP7A and ATP7B, notable for their role in disorders of copper deficiency and toxicity, Menkes and Wilson’s disease, respectively. Metallothioneins and Cu/Zn superoxide dismutase can protect against excess copper in cells. It is clear too, increasing age, environmental and lifestyle factors impact on brain copper. Studies on AD suggest an important role for copper in the brain, with some AD therapies focusing on mobilising copper in AD brains. The transport of copper into the brain is complex and involves numerous players, including amyloid precursor protein, Aβ peptide and cholesterol.

Keywords

Simvastatin Amyloid Precursor Protein Copper Level Copper Transporter Copper Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Amaravadi R, Glerum DM, Tzagoloff A (1997) Isolation of a cDNA encoding the human homolog of COX17, a yeast gene essential for mitochondrial copper recruitment. Hum Genet 99:329–333CrossRefGoogle Scholar
  2. Askwith C, Eide D, Van Ho A, Bernard PS, Li L, Davis-Kaplan S, Sipe DM, Kaplan J (1994) The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76:403–410CrossRefGoogle Scholar
  3. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI (1998) Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 273:12817–12826CrossRefGoogle Scholar
  4. Bayer TA, Schafer S, Simons A, Kemmling A, Kamer T, Tepest R, Eckert A, Schussel K, Eikenberg O, Sturchler-Pierrat C, Abramowski D, Staufenbiel M, Multhaup G (2003) Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice. Proc Natl Acad Sci USA 100:14187–14192CrossRefADSGoogle Scholar
  5. Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997) The cellular prion protein binds copper in vivo. Nature 390:684–687CrossRefADSGoogle Scholar
  6. Buchman C, Skroch P, Welch J, Fogel S, Karin M (1989) The CUP2 gene product, regulator of yeast metallothionein expression, is a copper-activated DNA-binding protein. Mol Cell Biol 9:4091–4095Google Scholar
  7. Bush AI (2000) Metals and neuroscience. Curr Opin Chem Biol 4:184–191CrossRefGoogle Scholar
  8. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676CrossRefGoogle Scholar
  9. Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R (2005) Statins cause intracellular accumulation of amyloid precursor protein, β-secretase-cleaved fragments, and amyloid β-peptide via an isoprenoid-dependent mechanism. J Biol Chem 280:18755–18770CrossRefGoogle Scholar
  10. Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, Gitlin JD (1997) The copper chaperone for superoxide dismutase. J Biol Chem 272:23469–23472CrossRefGoogle Scholar
  11. Danks DM (1995) Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WM, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 2211–2235Google Scholar
  12. Dancis A, Haile D, Yuan DS, Klausner RD (1994a) The Saccharomyces cerevisiae copper transport protein (Ctr1p). Biochemical characterization, regulation by copper, and physiologic role in copper uptake. J Biol Chem 269:25660–25667Google Scholar
  13. Dancis A, Yuan DS, Haile D, Askwith C, Eide D, Moehle C, Kaplan J, Klausner RD (1994b) Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell 76:393–402CrossRefGoogle Scholar
  14. de Silva D, Davis-Kaplan S, Fergestad J, Kaplan J (1997) Purification and characterization of Fet3 protein, a yeast homologue of ceruloplasmin. J Biol Chem 272:14208–14213CrossRefGoogle Scholar
  15. De Silva DM, Askwith CC, Eide D, Kaplan J (1995) The FET3 gene product required for high affinity iron transport in yeast is a cell surface ferroxidase. J Biol Chem 270:1098–1101CrossRefGoogle Scholar
  16. Glerum DM, Shtanko A, Tzagoloff A (1996) Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase. J Biol Chem 271:14504–14509CrossRefGoogle Scholar
  17. Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD (1995) Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci USA 92:2539–2543CrossRefADSGoogle Scholar
  18. Hesse L, Beher D, Masters CL, Multhaup G (1994) The β A4 amyloid precursor protein binding to copper. FEBS Lett 349:109–116CrossRefGoogle Scholar
  19. Horng YC, Cobine PA, Maxfield AB, Carr HS, Winge DR (2004) Specific copper transfer from the Cox17 metallochaperone to both Sco1 and Cox11 in the assembly of yeast cytochrome C oxidase. J Biol Chem 279:35334–35340CrossRefGoogle Scholar
  20. Hornshaw MP, McDermott JR, Candy JM (1995) Copper binding to the N-terminal tandem repeat regions of mammalian and avian prion protein. Biochem Biophys Res Commun 207:621–629CrossRefGoogle Scholar
  21. Kampfenkel K, Kushnir S, Babiychuk E, Inze D, Van Montagu M (1995) Molecular characterization of a putative Arabidopsis thaliana copper transporter and its yeast homologue. J Biol Chem 270:28479–28486CrossRefGoogle Scholar
  22. Karin M, Najarian R, Haslinger A, Valenzuela P, Welch J, Fogel S (1984) Primary structure and transcription of an amplified genetic locus: the CUP1 locus of yeast. Proc Natl Acad Sci USA 81:337–341CrossRefADSGoogle Scholar
  23. Klomp LW, Lin SJ, Yuan DS, Klausner RD, Culotta VC, Gitlin JD (1997) Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. J Biol Chem 272:9221–9226CrossRefGoogle Scholar
  24. Knight SA, Labbe S, Kwon LF, Kosman DJ, Thiele DJ (1996) A widespread transposable element masks expression of a yeast copper transport gene. Genes Dev 10:1917–1929CrossRefGoogle Scholar
  25. Lin SJ, Pufahl RA, Dancis A, O’Halloran TV, Culotta VC (1997) A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. J Biol Chem 272:9215–9220CrossRefGoogle Scholar
  26. Linder MC, Hazegh-Azam M (1996) Copper biochemistry and molecular biology. Am J Clin Nutr 63:797S–811SGoogle Scholar
  27. Macreadie IG, Johnson G, Schlosser T, Macreadie PI (2006) Growth inhibition of Candida species and Aspergillus fumigatus by statins. FEMS Microbiol Lett 262:9–13CrossRefGoogle Scholar
  28. Maynard CJ, Cappai R, Volitakis I, Cherny RA, White AR, Beyreuther K, Masters CL, Bush AI, Li QX (2002) Overexpression of Alzheimer’s disease amyloid- β opposes the age-dependent elevations of brain copper and iron. J Biol Chem 277:44670–44676CrossRefGoogle Scholar
  29. Ohgami RS, Campagna DR, McDonald A, Fleming MD (2006) The steap proteins are metalloreductases. Blood 108:1388–1394CrossRefGoogle Scholar
  30. Paik SR, Shin HJ, Lee JH, Chang CS, Kim J (1999) Copper(II)-induced self-oligomerization of alpha-synuclein. Biochem J 340:821–828CrossRefGoogle Scholar
  31. Paris I, Dagnino-Subiabre A, Marcelain K, Bennett LB, Caviedes P, Caviedes R, Azar CO, Segura-Aguilar J (2001) Copper neurotoxicity is dependent on dopamine-mediated copper uptake and one-electron reduction of aminochrome in a rat substantia nigra neuronal cell line. J Neurochem 77:519–529CrossRefGoogle Scholar
  32. Petris MJ, Mercer JF, Culvenor JG, Lockhart P, Gleeson PA, Camakaris J (1996) Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking. EMBO J 15:6084–6095Google Scholar
  33. Phinney AL, Drisaldi B, Schmidt SD, Lugowski S, Coronado V, Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J, Chishti MA, Cox DW, Mathews PM, Nixon RA, Carlson GA, St George-Hyslop P, Westaway D (2003) In vivo reduction of amyloid-β by a mutant copper transporter. Proc Natl Acad Sci USA 100:14193–14198CrossRefADSGoogle Scholar
  34. Portnoy ME, Schmidt PJ, Rogers RS, Culotta VC (2001) Metal transporters that contribute copper to metallochaperones in Saccharomyces cerevisiae. Mol Genet Genomics 265:873–882CrossRefGoogle Scholar
  35. Pufahl RA, Singer CP, Peariso KL, Lin SJ, Schmidt PJ, Fahrni CJ, Culotta VC, Penner-Hahn JE, O’Halloran TV (1997) Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science 278:853–856CrossRefADSGoogle Scholar
  36. Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O’Halloran TV (1999) Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284:805–808CrossRefADSGoogle Scholar
  37. Rees EM, Lee J, Thiele DJ (2004) Mobilization of intracellular copper stores by the ctr2 vacuolar copper transporter. J Biol Chem 279:54221–54229CrossRefGoogle Scholar
  38. Rees EM, Thiele DJ (2007) Identification of a Vacuole-associated metalloreductase and its role in Ctr2-mediated intracellular copper mobilization. J Biol Chem 282:21629–21638CrossRefGoogle Scholar
  39. Satoh K, Nakai T, Ichihara K (1994) Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in rat liver during ischemia. Eur J Pharmacol 270:365–369Google Scholar
  40. Schafer S, Pajonk FG, Multhaup G, Bayer TA (2007) Copper and clioquinol treatment in young APP transgenic and wild-type mice: effects on life expectancy, body weight, and metal-ion levels. J Mol Med 85:405–413CrossRefGoogle Scholar
  41. Snyder RD, Friedman MB (1998) Enhancement of cytotoxicity and clastogenicity of l-DOPA and dopamine by manganese and copper. Mutat Res 405:1–8Google Scholar
  42. Sparks DL, Schreurs BG (2003) Trace amounts of copper in water induce β-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease. Proc Natl Acad Sci USA 100:11065–11069CrossRefADSGoogle Scholar
  43. Spencer JP, Jenner A, Aruoma OI, Evans PJ, Kaur H, Dexter DT, Jenner P, Lees AJ, Marsden DC, Halliwell B (1994) Intense oxidative DNA damage promoted by L-dopa and its metabolites. Implications for neurodegenerative disease. FEBS Lett 353:246–250CrossRefGoogle Scholar
  44. Szczypka MS, Thiele DJ (1989) A cysteine-rich nuclear protein activates yeast metallothionein gene transcription. Mol Cell Biol 9:421–429Google Scholar
  45. Tabner BJ, Turnbull S, El-Agnaf O, Allsop D (2001) Production of reactive oxygen species from aggregating proteins implicated in Alzheimer’s disease, Parkinson’s disease and other neurodegenerative diseases. Curr Top Med Chem 1:507–517CrossRefGoogle Scholar
  46. Treiber C, Simons A, Strauss M, Hafner M, Cappai R, Bayer TA, Multhaup G (2004) Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer’s disease. J Biol Chem 279:51958–51964CrossRefGoogle Scholar
  47. van den Berghe PV, Folmer DE, Malingre HE, van Beurden E, Klomp AE, van de Sluis B, Merkx M, Berger R, Klomp LW (2007) Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake. Biochem J 407:49–59Google Scholar
  48. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) β-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741CrossRefGoogle Scholar
  49. Weiss KC, Linder MC (1985) Copper transport in rats involving a new plasma protein. Am J Physiol 249:E77–E88Google Scholar
  50. Westermeyer C, Macreadie IG (2007) Simvastatin reduces ergosterol levels, inhibits growth and causes loss of mtDNA in Candida glabrata. FEMS Yeast Res 7:436–441CrossRefGoogle Scholar
  51. White AR, Multhaup G, Maher F, Bellingham S, Camakaris J, Zheng H, Bush AI, Beyreuther K, Masters CL, Cappai R (1999a) The Alzheimer’s disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures. J Neurosci 19:9170–9179Google Scholar
  52. White AR, Reyes R, Mercer JF, Camakaris J, Zheng H, Bush AI, Multhaup G, Beyreuther K, Masters CL, Cappai R (1999b) Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice. Brain Res 842:439–444CrossRefGoogle Scholar
  53. White AR, Zheng H, Galatis D, Maher F, Hesse L, Multhaup G, Beyreuther K, Masters CL, Cappai R (1998) Survival of cultured neurons from amyloid precursor protein knock-out mice against Alzheimer’s amyloid-β toxicity and oxidative stress. J Neurosci 18:6207–6217Google Scholar
  54. Winge DR, Nielson KB, Gray WR, Hamer DH (1985) Yeast metallothionein. Sequence and metal-binding properties. J Biol Chem 260:14464–14470Google Scholar
  55. Wolozin B, Wang SW, Li N-C, Lee A, Lee TA, Kazis LE (2007) Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med 5:20. doi: 10.1186/1741-7015-5-20 CrossRefGoogle Scholar
  56. Yamaguchi-Iwai Y, Stearman R, Dancis A, Klausner RD (1996) Iron-regulated DNA binding by the AFT1 protein controls the iron regulon in yeast. EMBO J 15:3377–3384Google Scholar
  57. Yuan DS, Stearman R, Dancis A, Dunn T, Beeler T, Klausner RD (1995) The Menkes/Wilson disease gene homologue in yeast provides copper to a ceruloplasmin-like oxidase required for iron uptake. Proc Natl Acad Sci USA 92:2632–2636CrossRefADSGoogle Scholar
  58. Zhou B, Gitschier J (1997) hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci USA 94:7481–7486CrossRefADSGoogle Scholar

Copyright information

© CSIRO 2007

Authors and Affiliations

  1. 1.CSIRO Molecular and Health Technologies and P-Health FlagshipParkvilleAustralia

Personalised recommendations