Molecular Neurobiology

, Volume 9, Issue 1–3, pp 83–91 | Cite as

Antibodies to different isoforms of the heavy neurofilament protein (NF-H) in normal aging and Alzheimer's disease

  • Lior Soussan
  • Kirill Tchernakov
  • Orit Bachar-Lavi
  • Tamar Yuvan
  • Eliyahu Wertman
  • Daniel M. Michaelson

Abstract

Sera of normal controls and of patients with neurological diseases contain antineurofilament antibodies. Recent studies suggest that biochemically and immunologically distinct subclasses of neurofilaments occur in different types of neurons. Alzheimer's disease (AD), the major cause of dementia, is associated with a marked degeneration of brain cholinergic neurons. In the present work we characterized the repertoire and age dependence of antineurofilament antibodies in normal sera and examined whether the degeneration of cholinergic neurons in AD is associated with serum antibodies directed specifically against the neurofilaments of mammalian cholinergic neurons. This was performed by immunoblot assays utilizing neurofilaments from the purely cholinergic bovine ventral root neurons and from the chemically heterogeneous bovine dorsal root neurons. Antibodies to the heavy neurofilament protein NF-H were detected in normal control sera. Their levels were significantly higher in older (aged 70–79) than in younger (aged 40–59) subjects. These antibodies bound similarly to bovine ventral root and dorsal root NF-H and their NF-H specificity was unchanged during aging. In contrast, the levels of IgG in AD sera that are directed against ventral root cholinergic NF-H were higher than those directed against the chemically heterogeneous dorsal root NF-H. Immunoblot experiments utilizing dephosphorylated ventral root and dorsal root NF-H and chymotryptic fragments of these molecules revealed that AD sera contain a repertoire of antimamalian NF-H IgG. A subpopulation of these antibodies binds to phosphorylated epitopes that are specifically enriched in ventral root cholinergic NF-H and that are located on the carboxy terminal domain of this molecule. The level of these anticholinergic NF-H IgG are significantly higher in AD sera than in those of both normal controls and patients with multi-infarct dementia.

Index Entries

Alzheimer's disease normal aging antibodies neurofilaments cholinergic 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Steinart D. M. and Roop D. R. (1988)Ann. Rev. Biochem. 57, 593–625.CrossRefGoogle Scholar
  2. 2.
    Robinson P. A. and Anderton B. H. (1988)Rev. Neurosci. 2, 1–41.Google Scholar
  3. 3.
    Myers M. W., Lazzarini R. A., Lee V. M.-Y., Schlaepfer, W. W., and Nelson D. L. (1987)EMBO J. 6, 1617–1626.PubMedGoogle Scholar
  4. 4.
    Julien J.-P., Meyer D., Mushynski W., and Grosveld F. (1986) inMolecular Aspects of Neurobiology, Montalcini et al., eds., Springer-Verlag, Berlin, pp. 176–181.Google Scholar
  5. 5.
    Jones S. M. and Williams R. C. (1982)J. Biol. Chem. 257, 9902–9905.PubMedGoogle Scholar
  6. 6.
    Carden M. J., Schlaepfer W. W., and Lee V. M.-Y. (1985)J. Biol. Chem. 260, 9805–9817.PubMedGoogle Scholar
  7. 7.
    Julien J.-P. and Mushynski W. E. (1982)J. Biol. Chem. 257, 10,467–10,470.Google Scholar
  8. 8.
    Berglund A. M. and Ryugo D. K. (1991)J. Comp. Neurol. 306, 393–408.PubMedCrossRefGoogle Scholar
  9. 9.
    Campbell N. J. and Morrison J. H. (1989)J. Comp. Neurol. 282, 191–205.PubMedCrossRefGoogle Scholar
  10. 10.
    Clark E. A. and Lee, V. M.-Y. (1991)J. Neurosci. Res. 30, 116–123.PubMedCrossRefGoogle Scholar
  11. 11.
    Faigon M., Hadas E., Alroy G., Chapman J., Auerbach J. M., and Michaelson D. M. (1991)J. Neurosci. Res. 29, 490–498.PubMedCrossRefGoogle Scholar
  12. 12.
    Szaro B. G., Whitnall M. H., and Gainer H. (1990)J. Comp. Neurol. 302, 220–235.PubMedCrossRefGoogle Scholar
  13. 13.
    Vickers J. C., Costa M., Vitadello M., Dahl D., and Marotta C. A. (1990)Neuroscience 39, 743–759.PubMedCrossRefGoogle Scholar
  14. 14.
    Sotelo J., Gibbs J. R., and Gajdusek D. C. (1980)Science 210, 190–196.PubMedCrossRefGoogle Scholar
  15. 15.
    Bahmanyar S., Liem R. K. H., Griffin I. W., and Gajdusek D. C. (1984)J. Neuropathol. Exp. Neurol. 43, 369–375.PubMedGoogle Scholar
  16. 16.
    Toh B., Gibbs C., Gajdusek D. C., Goudsmit J., and Dahl D. (1985)Proc. Natl. Acad. Sci. USA 82, 3485–3489.PubMedCrossRefGoogle Scholar
  17. 17.
    Kurki P., Helve T., Dahl D., and Virtanen I. (1986)J. Rheumatol. 13, 69–73.PubMedGoogle Scholar
  18. 18.
    Galbraith G. M. P., Emerson D., Fudenberg H. H., Gibbs C. J., and Gajdusek D. C. (1986)J. Clin. Invest. 78, 865–869.PubMedCrossRefGoogle Scholar
  19. 19.
    Brown R. H., Johnson D., Ogonowski M., and Weiner H. L. (1987)Neurology 37, 152–155.PubMedGoogle Scholar
  20. 20.
    Kumar M., Cohen D., and Eisdorfer C. (1988)Alzheimer Dis. Assoc. Disord. 2, 50–55.PubMedGoogle Scholar
  21. 21.
    Fudenberg H. H. and Singh V. K. (1988)Drug Dev. Res. 15, 165–174.CrossRefGoogle Scholar
  22. 22.
    Yates C. M., Simpson J., Maloney A. F. J., Gordon A., and Reid A. H. (1980)Lancet 11, 979.CrossRefGoogle Scholar
  23. 23.
    Coyle J. T., Price D. L., and Delong M. R. (1983)Science 219, 1184–1190.PubMedCrossRefGoogle Scholar
  24. 24.
    Chapman J., Bachar O., Korczyn A. D., Wertman E., and Michaelson D. M. (1988)J. Neurochem. 51, 479–485.PubMedCrossRefGoogle Scholar
  25. 25.
    Chapman J., Bachar O., Korczyn A. D., Wertman E., and Michaelson D. M. (1989)J. Neurosci. 9, 2710–2717.PubMedGoogle Scholar
  26. 26.
    Hassin-Baer S., Wertman E., Raphael M., Stark V., Chapman, J., and Michaelson D. M. (1992)Neurology 42, 551–555.PubMedGoogle Scholar
  27. 27.
    Sorenson K. and Brodbeck U. (1986)J. Immunol. Meth. 95, 291–293.CrossRefGoogle Scholar
  28. 28.
    Debus E., Flugge G., Weber K., and Osborn M. (1982)EMBO J. 1, 41–45.PubMedGoogle Scholar
  29. 29.
    Shaw G., Osborn M., and Weber K. (1986)Eur. J. Cell. Biol. 42, 1–9.PubMedGoogle Scholar
  30. 30.
    Chin T. K., Eagles P. A. M., and Magg A. (1983)Biochem. J. 215, 239–252.PubMedGoogle Scholar
  31. 31.
    McKhann G., Drachmann D., Folstein M., Katzman R., Price D., and Stadlan E. M. (1984)Neurology 34, 939–944.PubMedGoogle Scholar
  32. 32.
    Zemcov A., Barclay L. L., Brush D., and Blass J. P. (1984)J. Am. Geriatric Soc. 32, 801–823.Google Scholar
  33. 33.
    Berg L. (1984)Br. J. Psychiat. 145, 339–340.Google Scholar
  34. 34.
    Colton T. (1974)Statistics in Medicine, Little Brown Co., Boston.Google Scholar
  35. 35.
    Ingram C. R. K., Phegan J., and Blumental H. T. (1974)J. Gerontol. 29, 20–27.PubMedGoogle Scholar
  36. 36.
    Elizan T. S., Casals J., and Yahr M. D. (1983)J. Neurol. Sci. 59, 341–347.PubMedCrossRefGoogle Scholar
  37. 37.
    Sternberger L. A. and Sternberger N. H. (1983)Proc. Natl. Acad. Sci. USA 80, 6126–6130.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee V. M.-Y., Carden M. J., Schlaepfer W. W., and Trojanowski J. Q. (1987)J. Neurosci. 7, 3474–3488.PubMedGoogle Scholar
  39. 39.
    Dahl D., Labkovsky B, and Bigmani A. (1988)J. Comp. Neurol. 271, 445–450.PubMedCrossRefGoogle Scholar
  40. 40.
    Tchernakov K., Soussan L., Hassin-Baer S., Wertman E. and Michaelson D. M. (1993)Res. Immunol. 143, 671–675.Google Scholar
  41. 41.
    Foley P., Bradford H. F., Dochert M., Fillet H., Levine V. M., McEwen B., Bucht G., and Hardy J. (1988)J. Neurol. 235, 466–471.PubMedCrossRefGoogle Scholar
  42. 42.
    McRae A. and Dahlstrom A. (1992)Rev. Neurosci. 3, 79–98.Google Scholar
  43. 43.
    Sternberger N. H., Sternberger L. A., and Ulrich J. (1985)Proc. Natl. Acad. Sci. USA 82, 4274–4276.PubMedCrossRefGoogle Scholar
  44. 44.
    Iqbal K. and Grundke-Iqbal I. (1991)Mol. Neurobiol. 5, 399–410.PubMedGoogle Scholar
  45. 45.
    Lichtenberg-Kraag B., Mandelkow E. M., Biernat J., Steiner B., Schroter C., Gustke N., Meyer H. E., and Mandelkow E. (1992)Proc. Natl. Acad. Sci. USA 89, 5384–5388.PubMedCrossRefGoogle Scholar
  46. 46.
    Mashiah E., Mallory M., Hansen L., Alford M., Deteresa R., and Terry R. (1993)Am. J. Pathol. 142, 1–13.Google Scholar
  47. 47.
    Soussan L., Barzilai A., and Michaelson D. M. (1993)J. Neurochem. 62, 770–776.CrossRefGoogle Scholar
  48. 48.
    Chapman J., Alroy G., Weiss Z., Faigon M., Feldon J., and Michaelson D. M. (1991)Neuroscience 40, 297–305.PubMedCrossRefGoogle Scholar
  49. 49.
    Dubovik V., Faigon M., Feldon J., and Michaelson D. M. (1993)Neuroscience 56, 75–82.PubMedCrossRefGoogle Scholar
  50. 50.
    Eilam D., Szechtman H., Faigon M., Dubovik V., Feldon J., and Michaelson D. M. (1993)Neuroscience 56, 83–91.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1994

Authors and Affiliations

  • Lior Soussan
    • 1
  • Kirill Tchernakov
    • 1
  • Orit Bachar-Lavi
    • 1
  • Tamar Yuvan
    • 1
  • Eliyahu Wertman
    • 2
  • Daniel M. Michaelson
    • 1
  1. 1.Department of Biochemistry, The George S. Wise Faculty of Life SciencesTel Aviv UniversityRamat AvivIsrael
  2. 2.Department of NeurogeriatricsEzrat Nashim HospitalJerusalemIsrael

Personalised recommendations