Skip to main content

Advertisement

SpringerLink
Log in

Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The level of the apo-form of the copper enzyme ceruloplasmin (CP) is an established peripheral marker in diseases associated with copper imbalance. In view of the proposal that disturbances of copper homeostasis may contribute to neurodegeneration associated with Alzheimer’s disease (AD), the present work investigates, by Western blot and non-reducing SDS-PAGE followed by activity staining, the features of CP protein, and the copper/CP relationship in cerebrospinal fluid (CSF) and serum of AD patients. Results show that only a fraction of total copper is associated with CP in the CSF, at variance with serum, both in affected and in healthy individuals. Furthermore, a conspicuous amount of apo-ceruloplasmin and a decrease of CP oxidase activity characterize the CSF of the affected individuals, and confirm that an impairment of copper metabolism occurs in their central nervous system. In the CSF of AD patients the decrease of active CP, associated with the increase in the pool of copper not sequestered by this protein, may play a role in the neurodegenerative process.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aldred AR, Grimes A, Schreiber G, Mercer JF (1987) Rat ceruloplasmin. Molecular cloning and gene expression in liver, choroid plexus, yolk sac, placenta, and testis. J Biol Chem 262:2875–2878

    PubMed  CAS  Google Scholar 

  • Aldred AR, Brack CM, Schreiber G (1995) The cerebral expression of plasma protein genes in different species. Comp Biochem Physiol B Biochem Mol Biol 111:1–15

    Article  PubMed  CAS  Google Scholar 

  • Bielli P, Calabrese L (2002) Structure to function relationships in ceruloplasmin: a ‘moonlighting’ protein. Cell Mol Life Sci 59:1413–1427

    Article  PubMed  CAS  Google Scholar 

  • Hellman NE, Gitlin JD (2002) Ceruloplasmin metabolism and function. Ann Rev Nutr 22:439–458

    Article  CAS  Google Scholar 

  • Hellman NE, Kono S, Mancini GM, Hoogeboom AJ, de Jong GJ, Gitlin JD (2002) Mechanisms of copper incorporation into human ceruloplasmin. J Biol Chem 277:46632–46638

    Article  PubMed  CAS  Google Scholar 

  • Hochstrasser H, Tomiuk J, Walter U, Behnke S, Spiegel J, Kruger R, Becker G, Riess O, Berg D (2005) Functional relevance of ceruloplasmin mutations in Parkinson’s disease. FASEB J 19:1851–1853

    PubMed  CAS  Google Scholar 

  • Iwase T, Nishimura M, Sugimura H, Igarashi H, Ozawa F, Shinmura K, Suzuki M, Tanaka M, Kino I (1996) Localization of Menkes gene expression in the mouse brain; its association with neurological manifestations in Menkes model mice. Acta Neuropathol (Berl) 91:482–488

    Article  CAS  Google Scholar 

  • Jacobsson J, Jonsson PA, Andersen PM, Forsgren L, Marklund SL (2001) Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations. Brain 124:1461–1466

    Article  PubMed  CAS  Google Scholar 

  • Klomp LW, Farhangrazi ZS, Dugan LL, Gitlin JD (1996) Ceruloplasmin gene expression in the murine central nervous system. J Clin Invest 98:207–215

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX (2005) Metals and amyloid-beta in Alzheimer’s disease. Int J Exp Pathol 86:147–159

    Article  PubMed  CAS  Google Scholar 

  • Melo TM, Larsen C, White LR, Aasly J, Sjobakk TE, Flaten TP, Sonnewald U, Syversen T (2003) Manganese, copper, and zinc in cerebrospinal fluid from patients with multiple sclerosis. Biol Trace Elem Res 93:1–8

    Article  PubMed  CAS  Google Scholar 

  • Miyajima H, Fujimoto M, Kohno S, Kaneko E, Gitlin JD (1998) CSF abnormalities in patients with aceruloplasminemia. Neurology 51:1188–1190

    PubMed  CAS  Google Scholar 

  • Miyajima H, Kono S, Takahashi Y, Sugimoto M (2002) Increased lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains. Blood Cells Mol Dis 29:433–438

    Article  PubMed  CAS  Google Scholar 

  • Molina JA, Jimenez-Jimenez FJ, AguilarMeseguer MVI, Mateos-Vega CJ, Gonzalez-Munoz MJ, de Bustos F, Porta J, Orti-Pareja M, Zurdo M, Barrios E, Martinez-Para MC (1998) Cerebrospinal fluid levels of transition metals in patients with Alzheimer’s disease. J Neural Transm 105:479–488

    Article  PubMed  CAS  Google Scholar 

  • Musci G, Bonaccorsi di Patti MC, Fagiolo U, Calabrese L (1993) Age-related changes in human ceruloplasmin. Evidence for oxidative modifications. J Biol Chem 268:13388–13395

    PubMed  CAS  Google Scholar 

  • Pajonk FG, Kessler H, Supprian T, Hamzei P, Bach D, Schweickhardt J, Herrmann W, Obeid R, Simons A, Falkai P, Multhaup G, Bayer TA (2005) Cognitive decline correlates with low plasma concentrations of copper in patients with mild to moderate Alzheimer’s disease. J Alzheimers Dis 8:23–27

    PubMed  CAS  Google Scholar 

  • Qian Y, Tiffany-Castiglioni E, Welsh J, Harris ED (1998) Copper efflux from murine microvascular cells requires expression of the Menkes disease Cu-ATPase. J Nutr 128:1276–1282

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Schosinsky KH, Lehmann HP, Beeler MF (1974) Measurement of ceruloplasmin from its oxidase activity in serum by use of o-dianisidine dihydrochloride. Clin Chem 20:1556–1563

    PubMed  CAS  Google Scholar 

  • Serot JM, Bene MC, Faure GC (2003) Choroid plexus, aging of the brain, and Alzheimer’s disease. Front Biosci 8: s515–521

    Article  PubMed  Google Scholar 

  • Shim H, Harris ZL (2003) Genetic defects in copper metabolism. J Nutr 133:1527S–1531S

    PubMed  CAS  Google Scholar 

  • 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 (2006) Excess of non ceruloplasmin serum copper in AD correlates with MMSE, CSF β-AMYLOID and h-TAU. Neurology 67:76–82

    Article  PubMed  CAS  Google Scholar 

  • Terada K, Nakako T, Yang XL, Iida M, Aiba N, Minamiya Y, Nakai M, Sakaki T, Miura N, Sugiyama T (1998) Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA. J Biol Chem 273:1815–1820

    Article  PubMed  CAS  Google Scholar 

  • Walshe JM (2003) Wilson’s disease: the importance of measuring serum ceruloplasmin non-immunologically. Ann Clin Biochem 40:115–121

    Article  PubMed  CAS  Google Scholar 

  • Wand GS, May C, May V, Whitehouse PJ, Rapoport SJ, Eipper BA (1987) Alzheimer’s disease: low levels of peptide alpha-amidation activity in brain and CSF. Neurology 37:1057–1061

    PubMed  CAS  Google Scholar 

  • Yoshida K, Furihata K, Takeda S, Nakamura A, Yamamoto K, Morita H, Hiyamuta S, Ikeda S, Shimizu N, Yanagisawa N (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9:267–272

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was partially supported by grants from the Italian Ministry of Health to L. R and from AFaR foundation to R. S. Authors wish to thank the patients who participated in this study. Dr. Antonio Ciaccio, who provided blood and CSF samples from healthy individuals, and Dr. Francesco Passerelli, who provided blood and CSF samples from AD patients, are greatly acknowledged. Dr. Palma Mattioli performed the densitometric assays.

Author information

Authors and Affiliations

  1. Department of Biology, “Tor Vergata” University of Rome, Via della Ricerca Scientifica, 00133, Rome, Italy

    Concetta R. Capo, Mario Arciello & Luisa Rossi

  2. Department of Neuroscience, AFaR Fatebenefratelli Hospital, Rome, Italy

    Rosanna Squitti, Emanuele Cassetta & Paolo Maria Rossini

  3. Department of Biochemical Sciences, “La Sapienza” University of Rome, Rome, Italy

    Lilia Calabrese

Authors
  1. Concetta R. Capo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mario Arciello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosanna Squitti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emanuele Cassetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paolo Maria Rossini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lilia Calabrese
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luisa Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luisa Rossi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Capo, C.R., Arciello, M., Squitti, R. et al. Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients. Biometals 21, 367–372 (2008). https://doi.org/10.1007/s10534-007-9125-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-007-9125-4

Keywords

Search

Navigation