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. 1990 May;136(5):1069–1075.

Relative abundance of tau and neurofilament epitopes in hippocampal neurofibrillary tangles.

M L Schmidt 1, V M Lee 1, J Q Trojanowski 1
PMCID: PMC1877428  PMID: 1693468

Abstract

Neurofibrillary tangles (NFTs) derive, in part, from normal neuronal cytoskeletal proteins, ie, large portions of tau (tau) but only restricted segments of the peripheral domains of the high- and middle-molecular weight neurofilament subunits. To learn more about the events leading to the incorporation of tau and neurofilament epitopes into NFTs, the relative abundance of tau and NF determinants in these lesions was quantitatively analyzed in hippocampi from Alzheimer disease (AD) patients and age-matched controls using monoclonal antibodies specific for tau or for NF proteins. Immunostained NFTs appeared qualitatively the same in both AD and controls, ie, every epitope found in AD NFTs occurred also in the NFTs of the control patients. However, in hippocampi with only a few tangles, tau epitopes, but no NF epitopes, were detected in NFTs. In contrast, both tau and NF epitopes were present in those tangles that were found in hippocampi with abundant NFTs. Nevertheless, the number of tau-positive NFTs generally exceeded the number of NF-positive NFTs. These findings indicate that tau epitopes are more abundant than NF epitopes in NFTs and that the formation of NFTs may be linked to a derangement in the normal metabolism of tau that is more extensive than alterations in NF protein metabolism.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. 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]
  2. Braak H., Braak E., Grundke-Iqbal I., Iqbal K. Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci Lett. 1986 Apr 24;65(3):351–355. doi: 10.1016/0304-3940(86)90288-0. [DOI] [PubMed] [Google Scholar]
  3. Carden M. J., Schlaepfer W. W., Lee V. M. The structure, biochemical properties, and immunogenicity of neurofilament peripheral regions are determined by phosphorylation state. J Biol Chem. 1985 Aug 15;260(17):9805–9817. [PubMed] [Google Scholar]
  4. Crystal H., Dickson D., Fuld P., Masur D., Scott R., Mehler M., Masdeu J., Kawas C., Aronson M., Wolfson L. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease. Neurology. 1988 Nov;38(11):1682–1687. doi: 10.1212/wnl.38.11.1682. [DOI] [PubMed] [Google Scholar]
  5. Goedert M., Wischik C. M., Crowther R. A., Walker J. E., Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A. 1988 Jun;85(11):4051–4055. doi: 10.1073/pnas.85.11.4051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., Binder L. I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913–4917. doi: 10.1073/pnas.83.13.4913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Joachim C. L., Morris J. H., Selkoe D. J., Kosik K. S. Tau epitopes are incorporated into a range of lesions in Alzheimer's disease. J Neuropathol Exp Neurol. 1987 Nov;46(6):611–622. doi: 10.1097/00005072-198711000-00001. [DOI] [PubMed] [Google Scholar]
  8. Kahn J., Anderton B. H., Miller C. C., Wood J. N., Esiri M. M. Staining with monoclonal antibodies to neurofilaments distinguishes between subpopulations of neurofibrillary tangles, between groups of axons and between groups of dendrites. J Neurol. 1987 May;234(4):241–246. doi: 10.1007/BF00618257. [DOI] [PubMed] [Google Scholar]
  9. Khachaturian Z. S. Diagnosis of Alzheimer's disease. Arch Neurol. 1985 Nov;42(11):1097–1105. doi: 10.1001/archneur.1985.04060100083029. [DOI] [PubMed] [Google Scholar]
  10. Kondo J., Honda T., Mori H., Hamada Y., Miura R., Ogawara M., Ihara Y. The carboxyl third of tau is tightly bound to paired helical filaments. Neuron. 1988 Nov;1(9):827–834. doi: 10.1016/0896-6273(88)90130-4. [DOI] [PubMed] [Google Scholar]
  11. Kosik K. S., Crandall J. E., Mufson E. J., Neve R. L. Tau in situ hybridization in normal and Alzheimer brain: localization in the somatodendritic compartment. Ann Neurol. 1989 Sep;26(3):352–361. doi: 10.1002/ana.410260308. [DOI] [PubMed] [Google Scholar]
  12. Kosik K. S., Joachim C. L., Selkoe D. J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4044–4048. doi: 10.1073/pnas.83.11.4044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kosik K. S., Orecchio L. D., Binder L., Trojanowski J. Q., Lee V. M., Lee G. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron. 1988 Nov;1(9):817–825. doi: 10.1016/0896-6273(88)90129-8. [DOI] [PubMed] [Google Scholar]
  14. Ksiezak-Reding H., Davies P., Yen S. H. Alz 50, a monoclonal antibody to Alzheimer's disease antigen, cross-reacts with tau proteins from bovine and normal human brain. J Biol Chem. 1988 Jun 15;263(17):7943–7947. [PubMed] [Google Scholar]
  15. Ksiezak-Reding H., Dickson D. W., Davies P., Yen S. H. Recognition of tau epitopes by anti-neurofilament antibodies that bind to Alzheimer neurofibrillary tangles. Proc Natl Acad Sci U S A. 1987 May;84(10):3410–3414. doi: 10.1073/pnas.84.10.3410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ksiezak-Reding H., Yen S. H. Two monoclonal antibodies recognize Alzheimer's neurofibrillary tangles, neurofilament, and microtubule-associated proteins. J Neurochem. 1987 Feb;48(2):455–462. doi: 10.1111/j.1471-4159.1987.tb04114.x. [DOI] [PubMed] [Google Scholar]
  17. Lee V. M., Otvos L., Jr, Carden M. J., Hollosi M., Dietzschold B., Lazzarini R. A. Identification of the major multiphosphorylation site in mammalian neurofilaments. Proc Natl Acad Sci U S A. 1988 Mar;85(6):1998–2002. doi: 10.1073/pnas.85.6.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lee V. M., Otvos L., Jr, Schmidt M. L., Trojanowski J. Q. Alzheimer disease tangles share immunological similarities with multiphosphorylation repeats in the two large neurofilament proteins. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7384–7388. doi: 10.1073/pnas.85.19.7384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lee V. M., Page C. D., Wu H. L., Schlaepfer W. W. Monoclonal antibodies to gel-excised glial filament protein and their reactivities with other intermediate filament proteins. J Neurochem. 1984 Jan;42(1):25–32. doi: 10.1111/j.1471-4159.1984.tb09692.x. [DOI] [PubMed] [Google Scholar]
  20. Migheli A., Butler M., Brown K., Shelanski M. L. Light and electron microscope localization of the microtubule-associated tau protein in rat brain. J Neurosci. 1988 Jun;8(6):1846–1851. doi: 10.1523/JNEUROSCI.08-06-01846.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miller C. C., Brion J. P., Calvert R., Chin T. K., Eagles P. A., Downes M. J., Flament-Durand J., Haugh M., Kahn J., Probst A. Alzheimer's paired helical filaments share epitopes with neurofilament side arms. EMBO J. 1986 Feb;5(2):269–276. doi: 10.1002/j.1460-2075.1986.tb04209.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nukina N., Kosik K. S., Selkoe D. J. Recognition of Alzheimer paired helical filaments by monoclonal neurofilament antibodies is due to crossreaction with tau protein. Proc Natl Acad Sci U S A. 1987 May;84(10):3415–3419. doi: 10.1073/pnas.84.10.3415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Papasozomenos S. C., Binder L. I. Phosphorylation determines two distinct species of Tau in the central nervous system. Cell Motil Cytoskeleton. 1987;8(3):210–226. doi: 10.1002/cm.970080303. [DOI] [PubMed] [Google Scholar]
  24. Papasozomenos S. C. Tau protein immunoreactivity in dementia of the Alzheimer type. I. Morphology, evolution, distribution, and pathogenetic implications. Lab Invest. 1989 Jan;60(1):123–137. [PubMed] [Google Scholar]
  25. Perry G., Rizzuto N., Autilio-Gambetti L., Gambetti P. Paired helical filaments from Alzheimer disease patients contain cytoskeletal components. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3916–3920. doi: 10.1073/pnas.82.11.3916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Roher A. E., Palmer K. C., Chau V., Ball M. J. Isolation and chemical characterization of Alzheimer's disease paired helical filament cytoskeletons: differentiation from amyloid plaque core protein. J Cell Biol. 1988 Dec;107(6 Pt 2):2703–2716. doi: 10.1083/jcb.107.6.2703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schmidt M. L., Carden M. J., Lee V. M., Trojanowski J. Q. Phosphate dependent and independent neurofilament epitopes in the axonal swellings of patients with motor neuron disease and controls. Lab Invest. 1987 Mar;56(3):282–294. [PubMed] [Google Scholar]
  28. Schmidt M. L., Gur R. E., Gur R. C., Trojanowski J. Q. Intraneuronal and extracellular neurofibrillary tangles exhibit mutually exclusive cytoskeletal antigens. Ann Neurol. 1988 Feb;23(2):184–189. doi: 10.1002/ana.410230212. [DOI] [PubMed] [Google Scholar]
  29. Schmidt M. L., Lee V. M., Hurtig H., Trojanowski J. Q. Properties of antigenic determinants that distinguish neurofibrillary tangles in progressive supranuclear palsy and Alzheimer's disease. Lab Invest. 1988 Oct;59(4):460–466. [PubMed] [Google Scholar]
  30. Schmidt M. L., Lee V. M., Trojanowski J. Q. Analysis of epitopes shared by Hirano bodies and neurofilament proteins in normal and Alzheimer's disease hippocampus. Lab Invest. 1989 Apr;60(4):513–522. [PubMed] [Google Scholar]
  31. Trojanowski J. Q., Schmidt M. L., Otvos L., Jr, Gur R. C., Gur R. E., Hurtig H., Lee V. M. Selective expression of epitopes in multiphosphorylation repeats of the high and middle molecular weight neurofilament proteins in Alzheimer neurofibrillary tangles. Ann Med. 1989;21(2):113–116. doi: 10.3109/07853898909149196. [DOI] [PubMed] [Google Scholar]
  32. Trojanowski J. Q., Schuck T., Schmidt M. L., Lee V. M. Distribution of tau proteins in the normal human central and peripheral nervous system. J Histochem Cytochem. 1989 Feb;37(2):209–215. doi: 10.1177/37.2.2492045. [DOI] [PubMed] [Google Scholar]
  33. Wischik C. M., Novak M., Thøgersen H. C., Edwards P. C., Runswick M. J., Jakes R., Walker J. E., Milstein C., Roth M., Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4506–4510. doi: 10.1073/pnas.85.12.4506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wolozin B. L., Pruchnicki A., Dickson D. W., Davies P. A neuronal antigen in the brains of Alzheimer patients. Science. 1986 May 2;232(4750):648–650. doi: 10.1126/science.3083509. [DOI] [PubMed] [Google Scholar]
  35. Wood J. G., Mirra S. S., Pollock N. J., Binder L. I. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau) Proc Natl Acad Sci U S A. 1986 Jun;83(11):4040–4043. doi: 10.1073/pnas.83.11.4040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yamaguchi H., Morimatsu M., Hirai S., Takahashi K. Alzheimer's neurofibrillary tangles are penetrated by astroglial processes and appear eosinophilic in their final stages. Acta Neuropathol. 1987;72(3):214–217. doi: 10.1007/BF00691092. [DOI] [PubMed] [Google Scholar]

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