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Serum levels of the iron binding protein p97 are elevated in Alzheimer′s disease

Nature Medicine volume 2, pages 1230–1235 (1996)Cite this article

Abstract

Alzheimer′s disease is a progressive and incurable disease whose prevalence increases dramatically with age. A biochemical marker for monitoring the onset and progression of the disease would be a valuable tool for disease management. In addition, such a marker might be used as an end point in clinical intervention protocols. Here we provide evidence that the soluble form of the iron binding protein p97 is found in elevated amounts in the serum of Alzheimer′s patients compared with healthy controls. This biochemical marker has the potential for identifying subjects afflicted with the disease and possibly for monitoring the onset and longitudinal progression of the disease.

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References

  1. Goedert, M., Spillantini, M.G., Cairns, N.J. & Crowther, R.A. Tau protein of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron 8, 156–160 (1992).

    Article  Google Scholar 

  2. Selkoe, D.J. The molecular pathology of Alzheimer's disease. Neuron 6, 487–498 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Terry, R.D., Masliah, E. & Salmon, D.P. Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neural. 30, 572–580 (1991).

    Article  CAS  Google Scholar 

  4. Blass, J.P. Pathophysiology of Alzheimer's syndrome. Neurology 43, S25–38 (1993).

    Google Scholar 

  5. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease — Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34, 939–944 (1984).

    Article  CAS  PubMed  Google Scholar 

  6. Shoji, M. et al. Production of the Alzheimer amyloid beta protein by normal proteolytic cleavage. Science 258, 126–129 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Nakamura, T. et al. Amyloid b protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer's disease. Ann. Neurol 36, 903–911 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Roher, A.E. et al. Structural alterations in the peptide backbone of β-amyloid core protein may account for its deposition and stability in Alzheimer's disease. J. Biol. Chem. 268, 3072–3083 (1993).

    CAS  PubMed  Google Scholar 

  9. Motter, R. et al. Reduction of β-amyloid peptide42, in the cerebrospinal fluid of patients with Alzheimer's disease. Ann. Neurol. 38, 643–648 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Van Nostrand, W.E. et al. Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer patients. Proc. Natl. Acad. Sci. USA 89, 2551–2555 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Palmert, M.R. et al. Soluble derivatives of the beta amyloid protein precursor in cerebrospinal fluid. Neurol. 40, 1028–1034 (1990).

    Article  CAS  Google Scholar 

  12. Kitaguchi, N. et al. Determination of amyloid beta protein precursors harboring active form of protease inhibitor domains in cerebrospinal fluid in Alzheimer′s disease patients by a trypsin antibody sandwich ELISA. Biochem. Biophys. Res. Commun. 166, 1453–1459 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. Vigo-Pelfrey, C. et al. Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer′s disease. Neurology 45, 788–793 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Vandermeeren, M. et al. Detection of tau proteins in normal and Alzheimer′s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J. Neurochem. 61, 1828–1834 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Abraham, C.R., Selkoe, D.J. & Potter, H. Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer′s disease. Cell 52, 487–501 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Wang, G.P. et al. Alzheimer′s disease: Paired helical filament immunoreactivity in cerebrospinal fluid. Acta Neuropathol.(Berl.) 82, 6–12 (1991).

    Article  CAS  Google Scholar 

  17. Sanders, A.M. et al. Association of apolipoprotein E allele 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1467–1472 (1993).

    Article  Google Scholar 

  18. Murrell, J., Farlow, M., Ghetti, B. & Benson, M.D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer′s disease. Science 254, 97–99 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Karlinsky, H. et al. Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation of codon of the beta amyloid precursor protein gene. Neurology 42, 1445–1453 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Schellenberg, G.D. et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258, 668–671 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Sherrington, R. et al. Cloning of a gene bearing missense mutations in the early onset of familial Alzheimer′s disease. Nature 375, 754–760 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Levy-Lahad, E. et al. Candidate genes for the chromosome 1 familial Alzheimer′s disease locus. Science 269, 973–977 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Rogaev, E.I. et al. Familial Alzheimer′s disease in kindreds with missense mutations in a gene on chromosome 1 related to Alzheimer′s disease type 3 gene. Nature 376, 775–778 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Strittmatter, W.J. et al. Apolipoprotein E: High avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer's disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brown, J.P., Nishiyama, K., Hellström, I. & Hellström, K.E. Structural characterization of human-melanoma-associated antigen p97 with monoclonal antibodies. J. Immunol. 127, 539–546 (1981).

    CAS  PubMed  Google Scholar 

  26. Baker, E.N., Rumball, S.V. & Anderson, B.F. Insights into structure and function from studies on lactoferrin. Trends Blochetn. Sci. 12, 350–353 (1987).

    Article  CAS  Google Scholar 

  27. Kennard, M.L., Richardson, D.R., Gabathuler, R., Ponka, P. & Jefferies, W.A. A novel iron uptake mechanism mediated by GPI-anchored human p97. EMBO J. 14, 4178–4186 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Food, M.R. et al. Transport and expression in human melanomas of a transferrinlike glycosylphospatidylinositol-anchored protein. J. Biol. Chem. 269, 3034–3040 (1994).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Jefferies, W.A. et al. Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease express melanotransferrin. Brain Res. 712, 122–126 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Kennard, M.L., Food, M.R., Jefferies, W.A. & Piret, J.M. Controlled process to recover heterologous glycosylphosphatidylinositol membrane anchored proteins from CHO cells. Biotech. Bioeng. 42, 480–486 (1993).

    Article  CAS  Google Scholar 

  32. Brown, J.P., Woodbury, E.G., Hart, C.E., Hellström, I. & Hellströ, K.E. Quantitative analysis of melanoma-associated antigen p97 in normal neoplastic tissues. Proc. Natl. Acad. Sci. USA 78, 539–543 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Connor, J.R., Menzies, S.L., St Martin, S.M. & Mufson, E.J. A histochemical study of iron, transfcrrin and ferritin in Alzheimer′s disease brains. J. Neurosci. Res. 31, 75–83 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Gerlach, M., Ben-Shachar, D., Riederer, P. & Youdim, M.B.H. Altered brain metabolism of iron as a cause of neurodegenerative diseases. J. Neurochem. 63, 793–807 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Multhaup, G. et al. The amyloid precursor protein of Alzheimer's disease in the reduction of copper (II) to copper (I). Science 271, 1406–1409 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Dedman, D.J. et al. Iron and aluminium in relation to brain ferritin in normal individuals and Alzheimer′s disease and chronic real-dialysis patients. Biochem. J. 287, 509–514 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mantyh, P.W. et al. Aluminum, iron and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J. Neurochem. 61, 1171–1174 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Bush, A.I. et al. Zinc and Alzheimer′s disease. Science 268, 1921–1922 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Ehmann, W.D. et al. Brain trace elements in Alzheimer′s disease. Neumtoxicology 7, 195–206 (1986).

    CAS  Google Scholar 

  40. Robinson, S.R., Noone, D.F., Kril, J. & Halliday, G.M. Most amyloid plaques contain ferritin rich cells. Alzheimer′s Res. 1, 191–196 (1996).

    Google Scholar 

  41. Grundke-Iqbal, I. et al. Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia. Acta Neumpathalogica. 81, 105–110 (1990).

    Article  CAS  Google Scholar 

  42. Good, P.F., Perl, D.P., Bierer, L.M. & Schmeidler, J. Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer′s disease. Ann. Neural 31, 286–292 (1992).

    Article  CAS  Google Scholar 

  43. McLachlan, D.R.C. et al. Intramuscular desferroxamine in patients with Alzheimer′s disease. Lancet 337, 1304–1308 (1991).

    Article  Google Scholar 

  44. Bodovitz, S., Faltudo, M.T., Frail, F.E. & Klein, W.L. Iron levels modulate alpha-sec-retase cleavage of amyloid precursor protein. J. Neuruchem. 64, 307–315 (1995).

    Article  CAS  Google Scholar 

  45. Zubcnko, G.S. et al. Clinically silent mutation in the putative iron-response element in exon 17 of the beta-amyloid precursor protein gene. J. Neuroputhol. Exp. Neurol. 51, 459–463 (1992).

    Article  Google Scholar 

  46. Jolley, M. et al. Particle concentration fluorescence immunoassay (PCFIA): A new rapid immunoassay technique with high sensitivity. J. Imnunnol. Methods 67, 21–35 (1984).

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Biotechnology Laboratory and the Departments of Medical Genetics, Microbiology and Immunology, and Zoology, University of British Columbia, Room 237, Wesbrook Building, 6174 University Boulevard, Vancouver, British Columbia, Canada, V6T 1Z3

    Malcolm L. Kennard & Wilfred A. Jefferies

  2. Division of Neurology, Department of Medicine, University of British Columbia, Room S193, Vancouver Hospital, and Health Sciences Centre, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada, V6T 2B5

    Howard Feldman

  3. Department of Neurology, School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260, Japan

    Tatsuo Yamada

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  1. Malcolm L. Kennard
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  2. Howard Feldman
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  3. Tatsuo Yamada
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  4. Wilfred A. Jefferies
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Kennard, M., Feldman, H., Yamada, T. et al. Serum levels of the iron binding protein p97 are elevated in Alzheimer′s disease. Nat Med 2, 1230–1235 (1996). https://doi.org/10.1038/nm1196-1230

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