Skip to main content

Metal Dysfunction in Alzheimer’s Disease

  • Chapter
  • First Online:

Abstract

It has been recently established that oxidative stress plays a key role in neurodegeneration. Consequently, researchers have focused their attention on transition metals, as they are known to participate in biochemical reactions that produce free radicals. In Alzheimer’s disease (AD), in particular, in vitro and animal studies have uncovered the role of iron and copper in the disease’s pathogenesis, recently confirmed in clinical studies. However, the link between AD and metals has been mostly investigated with a focus on local accumulations in brain areas critical for AD. More recently, a wider view has emerged proposing a relationship between AD and systemic changes of metal metabolism, upon genetic variability. In this chapter, we describe the major functions of iron and copper in the body and summarize the reasons why we should closely monitor their dyshomeostases in AD.

Keywords

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.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Wyman S, Simpson RJ, McKie AT, Sharp PA. Dcytb (Cybrd1) functions as both a ferric and a cupric reductase in vitro. FEBS Lett. 2008;582(13):1901–6. doi:S0014-5793(08)00410-9 [pii] 10.1016/j.febslet.2008.05.010.

    Article  PubMed  CAS  Google Scholar 

  2. Sacher A, Cohen A, Nelson N. Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes. J Exp Biol. 2001;204(Pt 6):1053–61.

    PubMed  CAS  Google Scholar 

  3. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med. 2011;62:347–60. doi:10.1146/annurev-med-050109-142444.

    Article  PubMed  CAS  Google Scholar 

  4. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3. doi:1104742 [pii] 10.1126/science.1104742.

    Article  PubMed  CAS  Google Scholar 

  5. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr. 1996;63(5):797S–811.

    PubMed  CAS  Google Scholar 

  6. Brewer GJ. Toxicity of copper in drinking water. J Toxicol Environ Health B Crit Rev. 2010;13 (6):449–52; author reply 453–49. doi:925758771 [pii] 10.1080/10937404.2010.499732

  7. Kim BE, Nevitt T, Thiele DJ. Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol. 2008;4(3):176–85. doi:nchembio.72 [pii] 10.1038/nchembio.72.

    Article  PubMed  CAS  Google Scholar 

  8. Collins JF, Franck CA, Kowdley KV, Ghishan FK. Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum. Am J Physiol Gastrointest Liver Physiol. 2005;288(5):G964–71. doi:00489.2004 [pii] 10.1152/ajpgi.00489.2004.

    Article  PubMed  CAS  Google Scholar 

  9. Jacobs DS, Oxley DK, DeMott WR. Laboratory test handbook concise with disease index. 2nd ed. Hudson: Lexi-Comp Inc; 2002.

    Google Scholar 

  10. Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011;434(3):365–81. doi:BJ20101825 [pii] 10.1042/BJ20101825.

    Article  PubMed  CAS  Google Scholar 

  11. Aisen P. Transferrin receptor 1. Int J Biochem Cell Biol. 2004;36(11):2137–43. doi:10.1016/j.biocel.2004.02.007 S1357272504000615 [pii].

    Article  PubMed  CAS  Google Scholar 

  12. Lill R. Function and biogenesis of iron-sulphur proteins. Nature. 2009;460(7257):831–8. doi:nature08301 [pii] 10.1038/nature08301.

    Article  PubMed  CAS  Google Scholar 

  13. Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr. 2008;28:197–213. doi:10.1146/annurev.nutr.28.061807.155521.

    Article  PubMed  CAS  Google Scholar 

  14. Moos T, Rosengren Nielsen T, Skjorringe T, Morgan EH. Iron trafficking inside the brain. J Neurochem. 2007;103(5):1730–40. doi:JNC4976 [pii] 10.1111/j.1471-4159.2007.04976.x.

    Article  PubMed  CAS  Google Scholar 

  15. Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA. Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Brain Res. 2004;1001(1–2):108–17. doi:10.1016/j.brainres.2003.10.066 S0006899303041234 [pii].

    Article  PubMed  CAS  Google Scholar 

  16. Michalke B, Nischwitz V. Review on metal speciation analysis in cerebrospinal fluid-current methods and results: a review. Anal Chim Acta. 2010;682(1–2):23–36. doi:S0003-2670(10)01237-7 [pii] 10.1016/j.aca.2010.09.054.

    Article  PubMed  CAS  Google Scholar 

  17. Bucossi S, Ventriglia M, Panetta V, Salustri C, Pasqualetti P, Mariani S, Siotto M, Rossini PM, Squitti R. Copper in Alzheimer’s disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies. J Alzheimers Dis. 2011;24(1):175–85. doi:R474R375HXT67344 [pii] 10.3233/JAD-2010-101473.

    PubMed  CAS  Google Scholar 

  18. Choi BS, Zheng W. Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res. 2009;1248:14–21. doi:S0006-8993(08)02634-6 [pii] 10.1016/j.brainres.2008.10.056.

    Article  PubMed  CAS  Google Scholar 

  19. Schlief ML, Gitlin JD. Copper homeostasis in the CNS: a novel link between the NMDA receptor and copper homeostasis in the hippocampus. Mol Neurobiol. 2006;33(2):81–90. doi:MN:33:2:81 [pii] 10.1385/MN:33:2:81.

    Article  PubMed  CAS  Google Scholar 

  20. Gaggelli E, Kozlowski H, Valensin D, Valensin G. Copper homeostasis and neurodegenerative disorders (Alzheimer’s, prion, and Parkinson’s diseases and amyotrophic lateral sclerosis). Chem Rev. 2006;106(6):1995–2044. doi:10.1021/cr040410w.

    Article  PubMed  CAS  Google Scholar 

  21. Bielli P, Calabrese L. Structure to function relationships in ceruloplasmin: a ‘moonlighting’ protein. Cell Mol Life Sci. 2002;59(9):1413–27.

    Article  PubMed  CAS  Google Scholar 

  22. Hoogenraad T. Wilson’s disease. Amsterdam: Intermed Medical Publishers; 2001.

    Google Scholar 

  23. Madsen E, Gitlin JD. Copper and iron disorders of the brain. Annu Rev Neurosci. 2007;30:317–37. doi:10.1146/annurev.neuro.30.051606.094232.

    Article  PubMed  CAS  Google Scholar 

  24. Vassiliev V, Harris ZL, Zatta P. Ceruloplasmin in neurodegenerative diseases. Brain Res Brain Res Rev. 2005;49(3):633–40. doi:S0165-0173(05)00046-9 [pii] 10.1016/j.brainresrev.2005.03.003.

    Article  PubMed  CAS  Google Scholar 

  25. Schrag M, Mueller C, Oyoyo U, Smith MA, Kirsch WM. Iron, zinc and copper in the Alzheimer’s disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog Neurobiol. 2011;94(3):296–306. doi:S0301-0082(11)00072-4 [pii] 10.1016/j.pneurobio.2011.05.001.

    Article  PubMed  CAS  Google Scholar 

  26. Bartzokis G, Tishler TA. MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer’s and Huntington’s disease. Cell Mol Biol (Noisy-le-Grand). 2000;46(4):821–33.

    CAS  Google Scholar 

  27. Bush AI, Tanzi RE. Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics. 2008;5(3):421–32. doi:S1933-7213(08)00090-1 [pii] 10.1016/j.nurt.2008.05.001.

    Article  PubMed  CAS  Google Scholar 

  28. Squitti R. Metals in Alzheimer’s disease: a systemic perspective. Front Biosci. 2012;17:451–72. doi:3938 [pii].

    Article  CAS  Google Scholar 

  29. Atwood CS, Perry G, Zeng H, Kato Y, Jones WD, Ling KQ, Huang X, Moir RD, Wang D, Sayre LM, Smith MA, Chen SG, Bush AI. Copper mediates dityrosine cross-linking of Alzheimer’s amyloid-beta. Biochemistry. 2004;43(2):560–8. doi:10.1021/bi0358824.

    Article  PubMed  CAS  Google Scholar 

  30. Roberts BR, Ryan TM, Bush AI, Masters CL, Duce JA. The role of metallobiology and amyloid-beta peptides in Alzheimer’s disease. J Neurochem. 2012;120 Suppl 1:149–66. doi:10.1111/j.1471-4159.2011.07500.x.

    Article  PubMed  CAS  Google Scholar 

  31. Rogers JT, Lahiri DK. Metal and inflammatory targets for Alzheimer’s disease. Curr Drug Targets. 2004;5(6):535–51.

    Article  PubMed  CAS  Google Scholar 

  32. Moalem S, Percy ME, Andrews DF, Kruck TP, Wong S, Dalton AJ, Mehta P, Fedor B, Warren AC. Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am J Med Genet. 2000;93(1):58–66. doi:10.1002/1096-8628(20000703)93:1<58::AID-AJMG10>3.0.CO;2-L [pii].

    Article  PubMed  CAS  Google Scholar 

  33. Giambattistelli F, Bucossi S, Salustri C, Panetta V, Mariani S, Siotto M, Ventriglia M, Vernieri F, Dell’acqua ML, Cassetta E, Rossini PM, Squitti R. Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer’s disease. Neurobiol Aging. 2011. doi:S0197-4580(11)00062-5 [pii] 10.1016/j.neurobiolaging.2011.03.005.

    PubMed  Google Scholar 

  34. Bellingham SA, Lahiri DK, Maloney B, La Fontaine S, Multhaup G, Camakaris J. Copper depletion down-regulates expression of the Alzheimer’s disease amyloid-beta precursor protein gene. J Biol Chem. 2004;279(19):20378–86. doi:10.1074/jbc.M400805200 M400805200 [pii].

    Article  PubMed  CAS  Google Scholar 

  35. Squitti R, Salustri C, Siotto M, Ventriglia M, Vernieri F, Lupoi D, Cassetta E, Rossini PM. Ceruloplasmin/Transferrin ratio changes in Alzheimer’s disease. Int J Alzheimers Dis. 2010;2011:231595. doi:10.4061/2011/231595.

    PubMed  Google Scholar 

  36. Squitti R, Barbati G, Rossi L, Ventriglia M, Dal Forno G, Cesaretti S, Moffa F, Caridi I, Cassetta E, Pasqualetti P, Calabrese L, Lupoi D, Rossini PM. Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau. Neurology. 2006;67(1):76–82. doi:67/1/76 [pii] 10.1212/01.wnl.0000223343.82809.cf.

    Article  PubMed  CAS  Google Scholar 

  37. Zappasodi F, Salustri C, Babiloni C, Cassetta E, Del Percio C, Ercolani M, Rossini PM, Squitti R. An observational study on the influence of the APOE-epsilon4 allele on the correlation between ‘free’ copper toxicosis and EEG activity in Alzheimer disease. Brain Res. 2008;1215:183–9. doi:S0006-8993(08)00820-2 [pii] 10.1016/j.brainres.2008.03.066.

    Article  PubMed  CAS  Google Scholar 

  38. Squitti R, Ventriglia M, Barbati G, Cassetta E, Ferreri F, Dal Forno G, Ramires S, Zappasodi F, Rossini PM. ‘Free’ copper in serum of Alzheimer’s disease patients correlates with markers of liver function. J Neural Transm. 2007;114(12):1589–94. doi:10.1007/s00702-007-0777-6.

    Article  PubMed  CAS  Google Scholar 

  39. Ventriglia M, Bucossi S, Panetta V, Squitti R. Copper in Alzheimer’s disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies. J Alzheimers Dis. 2012. doi:39R1H6VR87U10373 [pii] 10.3233/JAD-2012-120244.

    Google Scholar 

  40. Rembach A, Doecke JD, Roberts BR, Watt AD, Faux NG, Volitakis I, Pertile KK, Rumble RL, Trounson BO, Fowler CJ, Wilson W, Ellis KA, Martins RN, Rowe CC, Villemagne VL, Ames D, Masters CL, Bush AI. Longitudinal analysis of serum copper and ceruloplasmin in Alzheimer’s disease. J Alzheimers Dis. 2012;2:8. doi:K107150570452374 [pii] 10.3233/JAD-121474.

    Google Scholar 

  41. Twomey PJ, Viljoen A, House IM, Reynolds TM, Wierzbicki AS. Copper:caeruloplasmin ratio. J Clin Pathol. 2007;60(4):441–2. doi:60/4/441 [pii] 10.1136/jcp.2006.041756.

    Article  PubMed  CAS  Google Scholar 

  42. Gardener S, Gu Y, Rainey-Smith SR, Keogh JB, Clifton PM, Mathieson SL, Taddei K, Mondal A, Ward VK, Scarmeas N, Barnes M, Ellis KA, Head R, Masters CL, Ames D, Macaulay SL, Rowe CC, Szoeke C, Martins RN. Adherence to a Mediterranean diet and Alzheimer’s disease risk in an Australian population. Transl Psychiatry. 2012;2:e164. doi:tp201291 [pii] 10.1038/tp.2012.91.

    Article  PubMed  CAS  Google Scholar 

  43. Tang WH, Hartiala J, Fan Y, Wu Y, Stewart AF, Erdmann J, Kathiresan S, Roberts R, McPherson R, Allayee H, Hazen SL. Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk. Arterioscler Thromb Vasc Biol. 2012;32(11):2803–12. doi:ATVBAHA.112.253930 [pii] 10.1161/ATVBAHA.112.253930.

    Article  PubMed  CAS  Google Scholar 

  44. Polimanti R, Piacentini S, Manfellotto D, Fuciarelli M. Human genetic variation of CYP450 superfamily: analysis of functional diversity in worldwide populations. Pharmacogenomics. 2012;13(16):1951–60. doi:10.2217/pgs.12.163.

    Article  PubMed  CAS  Google Scholar 

  45. Ballantyne KN, van Oven M, Ralf A, Stoneking M, Mitchell RJ, van Oorschot RA, Kayser M. MtDNA SNP multiplexes for efficient inference of matrilineal genetic ancestry within Oceania. Forensic Sci Int Genet. 2012;6(4):425–36. doi:S1872-4973(11)00183-9 [pii] 10.1016/j.fsigen.2011.08.010.

    Article  PubMed  CAS  Google Scholar 

  46. Mueller C, Schrag M, Crofton A, Stolte J, Muckenthaler MU, Magaki S, Kirsch W. Altered serum iron and copper homeostasis predicts cognitive decline in mild cognitive impairment. J Alzheimers Dis. 2012;29(2):341–50. doi:N021303923584N63 [pii] 10.3233/JAD-2011-111841.

    PubMed  CAS  Google Scholar 

  47. Lopez N, Tormo C, De Blas I, Llinares I, Alom J. Oxidative stress in Alzheimer’s disease and mild cognitive impairment with high sensitivity and specificity. J Alzheimers Dis. 2013;33(3):823–9. doi:W27083817P732L45 [pii] 10.3233/JAD-2012-121528.

    PubMed  CAS  Google Scholar 

  48. Gorgone G, Ursini F, Altamura C, Bressi F, Tombini M, Curcio G, Chiovenda P, Squitti R, Silvestrini M, Ientile R, Pisani F, Rossini PM, Vernieri F. Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: a correlation study in patients with cognitive impairment. Atherosclerosis. 2009;206(1):309–13. doi:S0021-9150(09)00155-5 [pii] 10.1016/j.atherosclerosis.2009.02.028.

    Article  PubMed  CAS  Google Scholar 

  49. White AR, Huang X, Jobling MF, Barrow CJ, Beyreuther K, Masters CL, Bush AI, Cappai R. Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. J Neurochem. 2001;76(5):1509–20.

    Article  PubMed  CAS  Google Scholar 

  50. Squitti R, Bressi F, Pasqualetti P, Bonomini C, Ghidoni R, Binetti G, Cassetta E, Moffa F, Ventriglia M, Vernieri F, Rossini PM. Longitudinal prognostic value of serum “free” copper in patients with Alzheimer disease. Neurology. 2009;72(1):50–5. doi:72/1/50 [pii] 10.1212/01.wnl.0000338568.28960.3f.

    Article  PubMed  CAS  Google Scholar 

  51. James SA, Volitakis I, Adlard PA, Duce JA, Masters CL, Cherny RA, Bush AI. Elevated labile Cu is associated with oxidative pathology in Alzheimer disease. Free Radic Biol Med. 2012;52(2):298–302. doi:S0891-5849(11)01110-5 [pii] 10.1016/j.freeradbiomed.2011.10.446.

    Article  PubMed  CAS  Google Scholar 

  52. Bucossi S, Polimanti R, Mariani S, Ventriglia M, Bonvicini C, Migliore S, Manfellotto D, Salustri C, Vernieri F, Rossini PM, Squitti R. Association of K832R and R952K SNPs of Wilson’s Disease Gene with Alzheimer’s Disease. J Alzheimers Dis. 2012;29(4):913–9. doi:D729J362Q40W53R3 [pii] 10.3233/JAD-2012-111997.

    PubMed  CAS  Google Scholar 

  53. Squitti R, Polimanti R. Copper Hypothesis in the Missing Hereditability of Sporadic Alzheimer’s Disease: ATP7B Gene as Potential Harbor of Rare Variants. J Alzheimers Dis. 2012;29(3):493–501. doi:NM01V338M14607R1 [pii] 10.3233/JAD-2011-111991.

    PubMed  CAS  Google Scholar 

  54. Arnal N, Cristalli DO, de Alaniz MJ, Marra CA. Clinical utility of copper, ceruloplasmin, and metallothionein plasma determinations in human neurodegenerative patients and their first-degree relatives. Brain Res. 2010;1319:118–30. doi:S0006-8993(09)02666-3 [pii] 10.1016/j.brainres.2009.11.085.

    Article  PubMed  CAS  Google Scholar 

  55. Brewer GJ, Kanzer SH, Zimmerman EA, Celmins DF, Heckman SM, Dick R. Copper and ceruloplasmin abnormalities in Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2010;25(6):490–7. doi:1533317510375083 [pii] 10.1177/1533317510375083.

    Article  PubMed  Google Scholar 

  56. Agarwal R, Kushwaha SS, Tripathi CB, Singh N, Chhillar N. Serum copper in Alzheimer’s disease and vascular dementia. Indian J Clin Biochem. 2008;23(4):369–74. doi:10.1007/s12291-008-0081-8 81 [pii].

    Article  PubMed  CAS  Google Scholar 

  57. Sedighi B, Shafa MA, Shariati M. A study of serum copper and ceruloplasmin in Alzheimer’s disease in Kerman, Iran. Neurol Asia. 2006;11:107–9.

    Google Scholar 

  58. Snaedal J, Kristinsson J, Gunnarsdottir S, Olafsdottir BM, Johannesson T. Copper, ceruloplasmin and superoxide dismutase in patients with Alzheimer’s disease. a case-control study. Dement Geriatr Cogn Disord. 1998;9(5):239–42. doi:dem09239 [pii].

    Article  PubMed  CAS  Google Scholar 

  59. Molaschi M, Ponzetto M, Bertacna B, Berrino E, Ferrario E. Determination of selected trace elements in patients affected by dementia. Arch Gerontol Geriatr. 1996;22 Suppl 1:39–42. doi:0167-4943(96)86910-X [pii] 10.1016/0167-4943(96)86910-X.

    Article  PubMed  Google Scholar 

  60. Squitti R, Pasqualetti P, Dal Forno G, Moffa F, Cassetta E, Lupoi D, Vernieri F, Rossi L, Baldassini M, Rossini PM. Excess of serum copper not related to ceruloplasmin in Alzheimer disease. Neurology. 2005;64(6):1040–6. doi:64/6/1040 [pii] 10.1212/01.WNL.0000154531.79362.23.

    Article  PubMed  CAS  Google Scholar 

  61. Squitti R, Ghidoni R, Scrascia F, Benussi L, Panetta V, Pasqualetti P, Moffa F, Bernardini S, Ventriglia M, Binetti G, Rossini PM. Free copper distinguishes mild cognitive impairment subjects from healthy elderly individuals. J Alzheimers Dis. 2011;23(2):239–48. doi:6716PK524717404N [pii] 10.3233/JAD-2010-101098.

    PubMed  CAS  Google Scholar 

  62. Walshe JM. Wilson’s disease: the importance of measuring serum caeruloplasmin non-immunologically. Ann Clin Biochem. 2003;40(Pt 2):115–21. doi:10.1258/000456303763046021.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rosanna Squitti Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Squitti, R., Siotto, M., Salustri, C., Polimanti, R. (2013). Metal Dysfunction in Alzheimer’s Disease. In: Praticὸ, D., Mecocci, P. (eds) Studies on Alzheimer's Disease. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-598-9_7

Download citation

Publish with us

Policies and ethics