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. 2002 Oct;110(Suppl 5):869–870. doi: 10.1289/ehp.02110s5869

Possible involvement of copper(II) in Alzheimer disease.

Teresa Kowalik-Jankowska 1, Monika Ruta-Dolejsz 1, Kornelia Wisniewska 1, Leszek Lankiewicz 1, Henryk Kozlowski 1
PMCID: PMC1241263  PMID: 12426149

Abstract

The beta-amyloid (Abeta) peptide is a principal component of insoluble amyloid plaques that are characteristic neuropathological features of Alzheimer disease (AD). The amyloid peptide also exists as a normal soluble protein that undergoes a pathogenic transition to an aggregated, fibrous form. This transition can be affected by extraneous proteinaceous elements and nonproteinaceous elements such as copper ions, which may promote aggregation and/or stabilization of the fibrils. Copper has been found in abnormally high concentrations in amyloid plaques and AD-affected neuropil, and copper-selective chelators have been shown to dissolve Abeta peptide from postmortem brain specimens. Although Cu(2+) is an essential element for life and the function of numerous enzymes is basic to neurobiology, free or incorrectly bound Cu(2+) can also catalyze generation of the most damaging radicals, such as hydroxyl radical, giving a chemical modification of the protein, alternations in protein structure and solubility, and oxidative damage to surrounding tissue.

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Selected References

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  1. Atwood C. S., Huang X., Moir R. D., Tanzi R. E., Bush A. I. Role of free radicals and metal ions in the pathogenesis of Alzheimer's disease. Met Ions Biol Syst. 1999;36:309–364. [PubMed] [Google Scholar]
  2. Atwood C. S., Moir R. D., Huang X., Scarpa R. C., Bacarra N. M., Romano D. M., Hartshorn M. A., Tanzi R. E., Bush A. I. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998 May 22;273(21):12817–12826. doi: 10.1074/jbc.273.21.12817. [DOI] [PubMed] [Google Scholar]
  3. Atwood C. S., Scarpa R. C., Huang X., Moir R. D., Jones W. D., Fairlie D. P., Tanzi R. E., Bush A. I. Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem. 2000 Sep;75(3):1219–1233. doi: 10.1046/j.1471-4159.2000.0751219.x. [DOI] [PubMed] [Google Scholar]
  4. Bancher C., Brunner C., Lassmann H., Budka H., Jellinger K., Wiche G., Seitelberger F., Grundke-Iqbal I., Iqbal K., Wisniewski H. M. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 1989 Jan 16;477(1-2):90–99. doi: 10.1016/0006-8993(89)91396-6. [DOI] [PubMed] [Google Scholar]
  5. Busciglio J., Gabuzda D. H., Matsudaira P., Yankner B. A. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2092–2096. doi: 10.1073/pnas.90.5.2092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bush A. I. Metals and neuroscience. Curr Opin Chem Biol. 2000 Apr;4(2):184–191. doi: 10.1016/s1367-5931(99)00073-3. [DOI] [PubMed] [Google Scholar]
  7. Camakaris J., Voskoboinik I., Mercer J. F. Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun. 1999 Aug 2;261(2):225–232. doi: 10.1006/bbrc.1999.1073. [DOI] [PubMed] [Google Scholar]
  8. Cappai R., White A. R. Amyloid beta. Int J Biochem Cell Biol. 1999 Sep;31(9):885–889. doi: 10.1016/s1357-2725(99)00027-8. [DOI] [PubMed] [Google Scholar]
  9. Cherny R. A., Atwood C. S., Xilinas M. E., Gray D. N., Jones W. D., McLean C. A., Barnham K. J., Volitakis I., Fraser F. W., Kim Y. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001 Jun;30(3):665–676. doi: 10.1016/s0896-6273(01)00317-8. [DOI] [PubMed] [Google Scholar]
  10. Cherny R. A., Legg J. T., McLean C. A., Fairlie D. P., Huang X., Atwood C. S., Beyreuther K., Tanzi R. E., Masters C. L., Bush A. I. Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion. J Biol Chem. 1999 Aug 13;274(33):23223–23228. doi: 10.1074/jbc.274.33.23223. [DOI] [PubMed] [Google Scholar]
  11. Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr. 2000 Feb;71(2):621S–629S. doi: 10.1093/ajcn/71.2.621s. [DOI] [PubMed] [Google Scholar]
  12. Esch F. S., Keim P. S., Beattie E. C., Blacher R. W., Culwell A. R., Oltersdorf T., McClure D., Ward P. J. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science. 1990 Jun 1;248(4959):1122–1124. doi: 10.1126/science.2111583. [DOI] [PubMed] [Google Scholar]
  13. Evans D. A., Funkenstein H. H., Albert M. S., Scherr P. A., Cook N. R., Chown M. J., Hebert L. E., Hennekens C. H., Taylor J. O. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA. 1989 Nov 10;262(18):2551–2556. [PubMed] [Google Scholar]
  14. Howlett D. R., Jennings K. H., Lee D. C., Clark M. S., Brown F., Wetzel R., Wood S. J., Camilleri P., Roberts G. W. Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide. Neurodegeneration. 1995 Mar;4(1):23–32. doi: 10.1006/neur.1995.0003. [DOI] [PubMed] [Google Scholar]
  15. Huang X., Atwood C. S., Hartshorn M. A., Multhaup G., Goldstein L. E., Scarpa R. C., Cuajungco M. P., Gray D. N., Lim J., Moir R. D. The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999 Jun 15;38(24):7609–7616. doi: 10.1021/bi990438f. [DOI] [PubMed] [Google Scholar]
  16. Joachim C. L., Selkoe D. J. The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease. Alzheimer Dis Assoc Disord. 1992 Spring;6(1):7–34. doi: 10.1097/00002093-199205000-00003. [DOI] [PubMed] [Google Scholar]
  17. Kowalik-Jankowska T., Ruta-Dolejsz M., Wiśniewska K., Łankiewicz L. Cu(II) interaction with N-terminal fragments of human and mouse beta-amyloid peptide. J Inorg Biochem. 2001 Sep;86(2-3):535–545. doi: 10.1016/s0162-0134(01)00226-4. [DOI] [PubMed] [Google Scholar]
  18. Liu S. T., Howlett G., Barrow C. J. Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease. Biochemistry. 1999 Jul 20;38(29):9373–9378. doi: 10.1021/bi990205o. [DOI] [PubMed] [Google Scholar]
  19. Lovell M. A., Robertson J. D., Teesdale W. J., Campbell J. L., Markesbery W. R. Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci. 1998 Jun 11;158(1):47–52. doi: 10.1016/s0022-510x(98)00092-6. [DOI] [PubMed] [Google Scholar]
  20. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245–4249. doi: 10.1073/pnas.82.12.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miura T., Suzuki K., Kohata N., Takeuchi H. Metal binding modes of Alzheimer's amyloid beta-peptide in insoluble aggregates and soluble complexes. Biochemistry. 2000 Jun 13;39(23):7024–7031. doi: 10.1021/bi0002479. [DOI] [PubMed] [Google Scholar]
  22. Multhaup G., Ruppert T., Schlicksupp A., Hesse L., Bill E., Pipkorn R., Masters C. L., Beyreuther K. Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide. Biochemistry. 1998 May 19;37(20):7224–7230. doi: 10.1021/bi980022m. [DOI] [PubMed] [Google Scholar]
  23. Multhaup G., Schlicksupp A., Hesse L., Beher D., Ruppert T., Masters C. L., Beyreuther K. The amyloid precursor protein of Alzheimer's disease in the reduction of copper(II) to copper(I) Science. 1996 Mar 8;271(5254):1406–1409. doi: 10.1126/science.271.5254.1406. [DOI] [PubMed] [Google Scholar]
  24. Otvos L., Jr, Szendrei G. I., Lee V. M., Mantsch H. H. Human and rodent Alzheimer beta-amyloid peptides acquire distinct conformations in membrane-mimicking solvents. Eur J Biochem. 1993 Jan 15;211(1-2):249–257. doi: 10.1111/j.1432-1033.1993.tb19893.x. [DOI] [PubMed] [Google Scholar]
  25. Price D. L., Sisodia S. S. Cellular and molecular biology of Alzheimer's disease and animal models. Annu Rev Med. 1994;45:435–446. doi: 10.1146/annurev.med.45.1.435. [DOI] [PubMed] [Google Scholar]
  26. Ruiz F. H., González M., Bodini M., Opazo C., Inestrosa N. C. Cysteine 144 is a key residue in the copper reduction by the beta-amyloid precursor protein. J Neurochem. 1999 Sep;73(3):1288–1292. doi: 10.1046/j.1471-4159.1999.0731288.x. [DOI] [PubMed] [Google Scholar]
  27. Simonian N. A., Coyle J. T. Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 1996;36:83–106. doi: 10.1146/annurev.pa.36.040196.000503. [DOI] [PubMed] [Google Scholar]
  28. Stadtman E. R. Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions. Annu Rev Biochem. 1993;62:797–821. doi: 10.1146/annurev.bi.62.070193.004053. [DOI] [PubMed] [Google Scholar]
  29. Yamada T., Sasaki H., Furuya H., Miyata T., Goto I., Sakaki Y. Complementary DNA for the mouse homolog of the human amyloid beta protein precursor. Biochem Biophys Res Commun. 1987 Dec 16;149(2):665–671. doi: 10.1016/0006-291x(87)90419-0. [DOI] [PubMed] [Google Scholar]

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