τ Protein and the Neurofibrillary Pathology of Alzheimer’s Disease

  • Michel Goedert
  • John Q. Trojanowski
  • Virginia M.-Y. Lee
Part of the Contemporary Neuroscience book series (CNEURO)


Alzheimer’s disease is characterized clinically by a progressive loss of memory and other cognitive functions, resulting in a profound dementia. The intellectual decline is accompanied by the progressive accumulation in the brain of insoluble fibrous material, extracellularly in the form of senile plaques, and intracellularly in the form of neurofibrillary lesions. Alzheimer’s disease is genetically heterogenous, with different primary causes leading to the same phenotype and neuropathology. It is therefore possible that the activation of several distinct pathological pathways can lead to the disease, with neuritic plaques and neurofibrillary lesions representing the points of convergence of these events. It follows that a study of the mechanisms that lead to the formation of plaques and neurofibrillary lesions is essential for an understanding of the pathogenesis of all forms of Alzheimer’s disease. The formation of neurofibrillary lesions is believed to lead to the symptoms of the disease, which result most probably from the degeneration of nerve cells in cerebral cortex and hippocampal formation, with ensuing neuronal cell loss and reduction in synapse numbers.


Paired Helical Filament Adult Human Brain Neuropil Thread Protein Phosphatase Activity Neurofibrillary Pathology 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Goedert, M. (1993) Tau protein and the neurofibrillary pathology of Alzheimer’s disease, Trends Neurosci. 16, 460–465.PubMedCrossRefGoogle Scholar
  2. 2.
    Lee, V. M.-Y. (1995) Disruption of the cytoskeleton in Alzheimer’s disease, Curr. Opinion Neurobiol. 5, 663–668.CrossRefGoogle Scholar
  3. 3.
    Kidd, M. (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease, Nature 197, 192–193.PubMedCrossRefGoogle Scholar
  4. 4.
    Braak, H. and Braak, E. (1991) Neuropathological stageing of Alzheimer-related changes, Acta Neuropathol. 82, 239–259.PubMedCrossRefGoogle Scholar
  5. 5.
    Arriagada, P. V., Growdon, J. H., Hedley-White, E. T., and Hyman, B. T. (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease, Neurology 42, 631–639.PubMedCrossRefGoogle Scholar
  6. 6.
    Dickson, D. W., Crystal, H. A., Mattiace, L. A., Masur, D. M., Blau, A. D., Davies, P., Yen, S.-H., and Aronson, M. K. (1991) Identification of normal and pathological aging in prospectively studied non-demented elderly humans, Neurobiol. Aging 13, 179–189.CrossRefGoogle Scholar
  7. 7.
    Kowall, N. W., Beal, M. F., Busciglio, J., Duffy, L. K., and Yankner, B. A. (1991) An in vivo model for the neurodegenerative effects of f3-amyloid and protection by substance P, Proc. Natl. Acad. Sci. USA 88, 7247–7251.PubMedCrossRefGoogle Scholar
  8. 8.
    Crowther, R. A. and Wischik, C. M. (1985) Image reconstruction of the Alzheimer paired helical filament, EMBO J. 4, 3661–3665.PubMedGoogle Scholar
  9. 9.
    Wischik, C. M., Novak, M., Thogersen, H. C., Edwards, P. C., Runswick, M. J., Jakes, R., Walker, J. E., Milstein, C., Roth, M., and Klug, A. (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease, Proc. Natl. Acad. Sci. USA 85, 4506–4510.PubMedCrossRefGoogle Scholar
  10. 10.
    Kondo, J., Honda, T., Mori, H., Hamada, Y., Miura, R., Ogawara, H., and Ihara, Y. (1988) The carboxyl third of tau is tightly bound to paired helical filaments, Neuron 1, 827–834.PubMedCrossRefGoogle Scholar
  11. 11.
    Greenberg, S. G. and Davies, P. (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis, Proc. Natl. Acad. Sci. USA 87, 5827–5831.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee, V. M.-Y., Balin, B. J., Otvos, L., and Trojanowski, J. Q. (1991) A68-a major subunit of paired helical filaments and derivatized forms of normal tau, Science 251, 675–678.PubMedCrossRefGoogle Scholar
  13. 13.
    Goedert, M., Spillantini, M. G., Cairns, N. J., and Crowther, R. A. (1992) Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms, Neuron 8, 159–168.PubMedCrossRefGoogle Scholar
  14. 14.
    Crowther, R. A. (1991) Straight and paired helical filaments in Alzheimer disease have a common structural unit, Proc. Natl. Acad. Sci. USA 88, 2288–2292.PubMedCrossRefGoogle Scholar
  15. 15.
    Goedert, M., Jakes, R., Spillantini, M. G., and Crowther, R. A. (1994) Tau protein and Alzheimer’s disease, in Microtubules ( Hyams, J. S. and Lloyd, C. W., eds.), Wiley-Liss, New York, pp. 183–200.Google Scholar
  16. 16.
    Binder, L. I., Frankfurter, A., and Rebhun, L. I. (1985) The distribution of tau in the mammalian central nervous system, J Cell Biol. 101, 1371–1378.PubMedCrossRefGoogle Scholar
  17. 17.
    Lee, G., Cowan, N., and Kirschner, M. (1988) The primary structure and heterogeneity of tau protein from mouse brain, Science 239, 285–288.PubMedCrossRefGoogle Scholar
  18. 18.
    Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E., and Klug, A. (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease, Proc. Natl. Acad. Sci. USA 85, 4051–4055.PubMedCrossRefGoogle Scholar
  19. 19.
    Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D., and Crowther, R. A. (1989) Multiple isoforms of human microtubule-associated protein tau. Sequences and localization in neurofibrillary tangles of Alzheimer’s disease, Neuron 3, 519–526.PubMedCrossRefGoogle Scholar
  20. 20.
    Goedert, M. and Jakes, R. (1990) Expression of separate isoforms of human tau protein: Correlation with the tau pattern in brain and effects on tubulin polymerization, EMBOJ. 9, 4225–4230.Google Scholar
  21. 21.
    Goedert, M., Spillantini, M. G., Potier, M. C., Ulrich, J., and Crowther, R. A. (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: Differential expression of tau protein mRNAs in human brain, EMBO J. 8, 393–399.PubMedGoogle Scholar
  22. 22.
    Butner, K. A. and Kirschner, M. W. (1991) Tau protein binds to microtubules through a flexible array of distributed weak sites, J. Cell Biol. 115, 717–730.PubMedCrossRefGoogle Scholar
  23. 23.
    Goode, B. L. and Feinstein, S. C. (1994) Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau, J. Cell Biol. 124, 769–782.PubMedCrossRefGoogle Scholar
  24. 24.
    Hirokawa, N., Shiomura,Y., and Ogabe, S. (1988) Tau proteins: The molecular structure and mode of binding on microtubules, J. Cell Biol. 107, 1449–1459.Google Scholar
  25. 25.
    Goedert, M., Spillantini, M. G., and Crowther, R. A. (1992) Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system, Proc. Natl. Acad. Sci. USA 89, 4378–4381.CrossRefGoogle Scholar
  26. 26.
    Couchie, D., Mavilia, C., Georgieff, I. S., Liem, R. K. H., Shelanski, M. L., and Nunez, J. (1992) Primary structure of high molecular weight tau present in the peripheral nervous system, Proc. Natl. Acad. Sci. USA 89, 4378–4381.PubMedCrossRefGoogle Scholar
  27. 27.
    Butler, M. and Shelanski, M. L. (1986) Microheterogeneity of microtubule-associated tau protein is due to differences in phosphorylation, J. Neurochem. 47, 1517–1522.PubMedCrossRefGoogle Scholar
  28. 28.
    Burack, M. A. and Halpain, S. (1996) Site-specific regulation of Alzheimer-like tau phosphorylation in living neurons, Neuroscience 72, 167–184.PubMedCrossRefGoogle Scholar
  29. 29.
    Poulter, L., Barratt, D., Scott, C. W., and Caputo, C. B. (1993) Locations and immunoreactivities of phosphorylation sites on bovine and porcine tau proteins and a PHF-tau fragment, J. Biol. Chem. 268, 9636–9644.PubMedGoogle Scholar
  30. 30.
    Watanabe, A., Hasegawa, M., Suzuki, M., Takio, K., Morishima-Kawashima, M., Titani, K., Arai, T., Kosik, K. S., and Ihara, Y. (1993) In vivo phosphorylation sites in fetal and adult rat tau, J. Biol. Chem. 268, 25712–25717.PubMedGoogle Scholar
  31. 31.
    Kanemura, K., Takio, K., Miura, R., Titani, K., and Ihara, Y. (1992) Fetal-type phosphorylation of the tau in paired helical filaments, J. Neurochem. 58, 1667–1675.CrossRefGoogle Scholar
  32. 32.
    Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q., and Lee, V. M.-Y. (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding, Neuron 10, 1089–1099.PubMedCrossRefGoogle Scholar
  33. 33.
    Kenessey, A. and Yen, S.-H. C. (1993) The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments, Brain Res. 629, 40–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Brion, J. P., Smith, C., Couck, A. M., Gallo, J. M., andAnderton, B. H. (1993) Developmental changes in tau phosphorylation: fetal tau is transiently phosphorylated in a manner similar to paired helical filament tau characteristic of Alzheimer’s disease, J Neurochem. 61, 2071–2080.PubMedCrossRefGoogle Scholar
  35. 35.
    Hasegawa, M., Watanabe, A., Takio, K., Suzuki, M., Arai, T., Titani, K., and Ihara, Y. (1993) Characterization of two distinct monoclonal antibodies to paired helical filaments: further evidence for fetal-type phosphorylation of the tau in paired helical filaments, J. Neurochem. 60, 2068–2077.PubMedCrossRefGoogle Scholar
  36. 36.
    Goedert, M., Jakes, R., Crowther, R. A., Cohen, P., Vanmechelen, E., Vandermeeren, M., and Cras, P. (1994) Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer’s disease: identification of phosphorylation sites in tau protein, Biochem. J. 301, 871–877.PubMedGoogle Scholar
  37. 37.
    Matsuo, E. S., Shin, R.-W., Bilingsley, M. L., Van de Voorde, A., O’Connor, M., Trojanowski, J. Q., and Lee, V. M.-Y. (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau, Neuron 13, 989–1002.PubMedCrossRefGoogle Scholar
  38. 37a.
    Otvos, L., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., and Lee, V. M.-Y. (1994) Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404, J. Neurosci. Res. 39, 669–673.PubMedCrossRefGoogle Scholar
  39. 38.
    Seubert, P., Mawal-Dewan, M., Barbour, R., Jakes, R., Goedert, M., Johnson, G. V. W., Litersky, J. M., Schenk, D., Lieberburg, I., Trojanowski, J. Q., and Lee, V. M.-Y. (1995) Detection of phosphorylated Ser262 in fetal tau, adult tau and paired helical filament tau, J. Biol. Chem. 270, 18917–18922.PubMedCrossRefGoogle Scholar
  40. 38a.
    Goedert, M., Jakes, R., and Vanmechelen, E. (1995) Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205, Neurosci. Lett. 189, 167–170.PubMedCrossRefGoogle Scholar
  41. 39.
    Ishiguro, K., Sato, K., Takamatsu, M., Park, J., Uchida, T., and Imahori, K. (1995) Analysis of phosphorylation of tau with antibodies specific for phosphorylation sites, Neurosci. Lett. 202, 81–84.PubMedCrossRefGoogle Scholar
  42. 40.
    Hasegawa, M., Jakes, R., Crowther, R. A., Lee, V. M.-Y., Ihara, Y., and Goedert, M. (1996) Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein, FEBS Lett. 384, 25–30.PubMedCrossRefGoogle Scholar
  43. 41.
    Drewes, G., Trinczek, B., Illenberger, S., Biernat, J., Schmitt-Ulms, G., Meyer, H. E., Mandelkow, E. M., and Mandelkow, E. (1995) Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark), J. Biol. Chem. 270, 7679–7688.PubMedCrossRefGoogle Scholar
  44. 42.
    Ledesma, M. D., Correas, I., Avila, J., and Diaz-Nido, J. (1992) Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau in Alzheimer’s disease, FEBS Leu. 308, 218–224.CrossRefGoogle Scholar
  45. 43.
    Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J. R, and Anderton, B. H. (1992) Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: Generation of paired helical filament epitopes and neuronal localization of the kinase, Neurosci. Leu. 147, 58–62.CrossRefGoogle Scholar
  46. 44.
    Mandelkow, E. M., Drewes, G., Biernat, J., Gustke, N., Van Lint, J., Vandenheede, J. R., and Mandelkow, E. (1992) Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau, FEBS Lett. 314, 315–321.PubMedCrossRefGoogle Scholar
  47. 45.
    Ishiguro, K., Shiratsuchi, A., Sato, S., Omori, A., Arioka, M., Kobayashi, S., Uchida, T., and Imahori, K. (1993) Glycogen synthase kinase-3ß is identical to tau protein kinase I generating several epitopes of paired helical filaments, FEBS Lett. 325, 167–172.PubMedCrossRefGoogle Scholar
  48. 46.
    Paudel, H. K., Lew, J., Zenobia, A., and Wang, J. H. (1993) Brain proline-directed kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer’s paired helical filaments, J. Biol. Chem. 268, 23512–23518.PubMedGoogle Scholar
  49. 47.
    Kobayashi, S., Ishiguro, K., Omori, A., Takamatsu, M., Arioka, M., Imahori, K., and Uchida, T. (1993) A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubules, FEBS Lett. 335, 171–175.PubMedCrossRefGoogle Scholar
  50. 48.
    Baumann, K., Mandelkow, E. M., Biernat, J., Piwnica-Worms, H., and Mandelkow, E. (1993) Abnormal Alzheimer’s-like phosphorylation of tau protein by cyclin-dependent kinases cdk2 and cdk5, FEBS Lett. 336, 417–424.PubMedCrossRefGoogle Scholar
  51. 49.
    Yang, S.-D., Yu, J.-S., Shiah, S.-G., and Huang, J.-J. (1994) Protein kinase FA/glycogen synthase kinase-3 alpha after heparin potentiation phosphorylates tau on sites abnormally phosphorylated in Alzheimer’s disease brain, J. Neurochem. 63, 1416–1425.PubMedCrossRefGoogle Scholar
  52. 50.
    Moreno, F. J., Medina, M., Pérez, M., Montejo de Garcini, E., and Avila, J. (1995) Glycogen synthase kinase-3 phosphorylates recombinant human tau protein at serine-262 in the presence of heparin (or tubulin), FEBS Lett. 372, 65–68.Google Scholar
  53. 51.
    Litersky, J. M., Johnson, G. V. W., Jakes, R., Goedert, M., Lee, M., and Seubert, P. (1996) Tau protein is phosphorylated by cAMP-dependent protein kinase and calcium/calmodulindependent protein kinase II within its microtubule-binding domains at Ser262 and Ser356, Biochem. J. 316, 655–660.PubMedGoogle Scholar
  54. 52.
    Goedert, M., Cohen, E. S., Jakes, R., and Cohen, P. (1992) p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer’s disease, FEBS Lett. 312, 95–99.Google Scholar
  55. 53.
    Goedert, M., Jakes, R., Qi, Z., Wang, J. H., and Cohen, P. (1995) Protein phosphatase 2A is the major enzyme in brain that dephosphorylates tau protein phosphorylated by proline-directed protein kinases or cAMP-dependent protein kinase, J. Neurochem. 65, 2804–2807.PubMedCrossRefGoogle Scholar
  56. 54.
    Szücs, K., Ledesma, M. D., Dombradi, V., Gergely, P., Avila, J., and Friedrich, P. (1994) Dephosphorylation of tau protein from Alzheimer’s disease patients, Neurosci. Lett. 165, 175–178.PubMedCrossRefGoogle Scholar
  57. 55.
    Fleming, L. M. and Johnson, G. V. W. (1995) Modulation of the phosphorylation state of tau in situ: the roles of calcium and cyclic AMP, Biochem. 1 309, 41–47.Google Scholar
  58. 56.
    Saito, T., Ishiguro, K., Uchida, T., Miyamoto, E., Kishimoto, T., and Hisanaga, S.-I. (1995) In situ dephosphorylation of tau by protein phosphatase 2A and 2B in fetal rat primary cultured neurons, FEBS Lett. 376, 238–242.PubMedCrossRefGoogle Scholar
  59. 57.
    Dupont-Wallois, L., Sautiere, P. E., Cocquerelle, C., Bailleul, B., Delacourte, A., and CailletBoudin, M. L. (1995) Shift from fetal-type to Alzheimer-type phosphorylated tau proteins in SKNSH-SY5Y cells treated with okadaic acid, FEBS Lett. 357, 197–201.PubMedCrossRefGoogle Scholar
  60. 58.
    Merrick, S. E., Demoise, D. C., and Lee, V. M.-Y. (1996) Site-specific dephosphorylation of tau protein at Ser/Thr 202/205 in response to microtubule depolymerization in cultured human neurons involves protein phosphatase 2A, J. Biol. Chem. 271, 5589–5594.PubMedCrossRefGoogle Scholar
  61. 59.
    Davis, D. A., Brion, J. P., Couck, A. M., Gallo, J. M., Hanger, D. P., Ladhani, K., Lewis, C., Miller, C. C. J., Rupniak, T., Smith, C., and Anderton, B. H. (1995) The phosphorylation state of the microtubule-associated protein tau as affected by glutamate, colchicine and ßamyloid in primary rat cortical neuronal cultures, Biochem. 1 309, 941–949.Google Scholar
  62. 59a.
    Arendt, T., Holzer, M., Fruth, R., Bruckner, M. K., and Gärtner, U. (1995) Paired helical filament-like phosphorylation of tau, deposition of ß/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A, Neuroscience 69, 691–698.PubMedCrossRefGoogle Scholar
  63. 60.
    Sontag, E., Nunbhadki-Craig, V., Bloom, G. S., and Mumby, M. C. (1995) A novel pool of protein phosphatase 2A is associated with microtubules and is regulated during the cell cycle, J. Cell Biol. 128, 1131–1144.PubMedCrossRefGoogle Scholar
  64. 60a.
    Weingarten, M. D., Lockwood, A. H., Hwo, S.-H., and Kirschner, M. W. (1975) A protein factor essential for microtubule assembly, Proc. Natl. Acad. Sci. USA 72, 1858–1862.PubMedCrossRefGoogle Scholar
  65. 61.
    Drechsel, D. N., Hyman, A. A., Cobb, M. H., and Kirschner, M. W. (1992) Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau, Mol. Cell. Biol. 3, 1141–1154.Google Scholar
  66. 62.
    Drubin, D. G. and Kirschner, M. W. (1986) Tau protein function in living cells, J. Cell Biol. 103, 2739–2746.PubMedCrossRefGoogle Scholar
  67. 63.
    Kanai, Y., Takemura, R., Oshima, T., Mori, H., Ihara, Y., Yanagisawa, M., Masaki, T., and Hirokawa, N. (1989) Expression of multiple tau isoforms and microtubule bundle formation in fibroblasts transfected with a single tau cDNA, J. Cell Biol. 109, 1173–1184.PubMedCrossRefGoogle Scholar
  68. 64.
    Knops, J., Kosik, K. S., Lee, G., Pardee, J. D., Cohen-Gould, L., and McColongue, L. (1991) Overexpression of tau in a nonneuronal cell induces long cellular processes, J. Cell Biol. 114, 725–733.PubMedCrossRefGoogle Scholar
  69. 65.
    Lee, G. and Rook, S. L. (1992) Expression of tau protein in non-neuronal cells: Microtubule binding and stabilization, J. Cell Sci. 102, 227–237.PubMedGoogle Scholar
  70. 66.
    Gallo, J. M., Hanger, D. P., Twist, E. C., Kosik, K. S., and Anderton, B. H. (1992) Expression and phosphorylation of a three-repeat isoform of tau in transfected non-neuronal cells, Biochem. J. 286, 399–404.PubMedGoogle Scholar
  71. 67.
    Kanai, Y., Chen, J., and Hirokawa, N. (1992) Microtubule bundling by tau proteins in vivo: Analysis of functional domains, EMBO J. 11, 3953–3961.Google Scholar
  72. 68.
    Lo, M. M. S., Fieles, A. W., Norris, T. E., Dargis, D. G., Caputo, C. B., Scott, C. W., Lee, V. M.-Y., and Goedert, M. (1993) Human tau isoforms confer distinct morphological and functional properties to stably transfected fibroblasts, Mol. Brain Res. 20, 209–220.PubMedCrossRefGoogle Scholar
  73. 69.
    Edson, K., Weisshaar, B., and Matus, A. (1993) Actin depolymerisation induces process formation in MAP2-transfected neuronal cells, Development 117, 689–700.PubMedGoogle Scholar
  74. 70.
    Caceres, A. and Kosik, K. S. (1990) Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons, Nature 343, 461–463.PubMedCrossRefGoogle Scholar
  75. 71.
    Hanemaaijer, R. and Ginzburg, I. (1991) Involvement of mature tau isoforms in the stabilization of neurites in PC12 cells, J. Neurosci. Res. 30, 163–171.PubMedCrossRefGoogle Scholar
  76. 72.
    Harada, A., Oguchi, K., Okabe, S., Kuno, J., Tereda, S., Ohshima, T., Sato-Yoshitake, R., Takei, Y., Noda, T., and Hirokawa, N. (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein, Nature 369, 488–491.PubMedCrossRefGoogle Scholar
  77. 73.
    Brion, J. P., Passareiro, H., Nunez, J., and Flament-Durand, J. (1985) Mise en évidence immunologique de la protéine tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d’Alzheimer, Arch. Biol. (Bruxelles) 95, 229–235.Google Scholar
  78. 74.
    Jakes, R., Novak, M., Davison, M., and Wischik, C. M. (1991) Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer’s disease, EMBO J. 10, 2725–2729.PubMedGoogle Scholar
  79. 75.
    Bondareff, W., Wischik, C. M., Novak, M., Amos, W. B., Klug, A., and Roth, M. (1990) Molecular analysis of neurofibrillary degeneration in Alzheimer’s disease: an immunohistochemical study, Am. J Pathol. 37, 711–723.Google Scholar
  80. 76.
    Wille, H., Drewes, G., Biernat, J., Mandelkow, E. M., and Mandelkow, E. (1992) Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro, J. Cell Biol. 118, 573–584.PubMedCrossRefGoogle Scholar
  81. 77.
    Crowther, R. A., Olesen, O. F., Jakes, R., and Goedert, M. (1992) The microtubule-binding repeats of tau protein assemble into filaments like those found in Alzheimer’s disease, FEBS Lett. 309, 199–202.PubMedCrossRefGoogle Scholar
  82. 78.
    Ksiezak-Reding, H. and Yen, S.-H. (1991) Structural stability of paired helical filaments requires microtubule-binding domains of tau: A model for self-association, Neuron 6, 717–728.PubMedCrossRefGoogle Scholar
  83. 79.
    Brion, J. P., Hanger, D. P., Bruce, M. T., Couck, A. M., Flament-Durand, J., and Anderton, B. H. (1991) Tau in Alzheimer neurofibrillary tangles: N- and C-terminal regions are differentially associated with paired helical filaments and the location of a putative abnormal phosphorylation site, Biochem. J. 273, 127–133.PubMedGoogle Scholar
  84. 80.
    Mori, H., Kondo, J., and Ihara, Y. (1987) Ubiquitin is a component of paired helical filaments in Alzheimer’s disease, Science 315, 1641–1644.CrossRefGoogle Scholar
  85. 81.
    Perry, G., Friedman, R., Shaw, G., and Chau, V. (1987) Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains, Proc. Natl. Acad. Sci. USA 84, 3033–3036.PubMedCrossRefGoogle Scholar
  86. 82.
    Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Titani, K., and Ihara, Y. (1993) Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments, Neuron 10, 1151–1160.PubMedCrossRefGoogle Scholar
  87. 83.
    Flament, S., Delacourte, A., Hémon, B., and Défossez, A. (1989) Characterization of two pathological tau protein variants in Alzheimer’s disease, J. Neurol. Sci. 92, 133–141.PubMedCrossRefGoogle Scholar
  88. 84.
    Greenberg, S. G., Davies, P., Schein, J. D., and Binder, L. I. (1992) Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau, J. Biol. Chem. 267, 564–569.PubMedGoogle Scholar
  89. 85.
    Liu, W-K., Dickson, D. W., andYen, S.-H. (1993) Heterogeneity of tau proteins in Alzheimer’s disease, Am. J Pathol. 142, 387–394.PubMedGoogle Scholar
  90. 86.
    Yoshida, H. and Ihara, Y. (1993) Tau in paired helical filament is functionally distinct from fetal tau: assembly incompetence of paired helical filament tau, J. Neurochem. 61, 1183–1186.PubMedCrossRefGoogle Scholar
  91. 87.
    Hasegawa, M., Morishima-Kawashima, M., Takio, K., Suzuki, M., Titani, K., and Ihara, Y. (1992) Protein sequence and mass spectrometric analyses of tau in the Alzheimer’s disease brain, J. Biol. Chem. 267, 17047–17054.PubMedGoogle Scholar
  92. 88.
    Goedert, M., Jakes, R., Crowther, R. A., Six, J., Lübke, U., Vandermeeren, M., Cras, P., Trojanowski, J. Q., and Lee, V. M.-Y. (1993) The abnormal phosphorylation of tau protein at serine 202 in Alzheimer disease recapitulates phosphorylation during development, Proc. Natl. Acad. Sci. USA 90, 5066–5070.PubMedCrossRefGoogle Scholar
  93. 89.
    Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Yoshida, H., Titani, K., and Ihara, Y. (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau, J. Biol. Chem. 270, 823–829.PubMedCrossRefGoogle Scholar
  94. 90.
    Drewes G., Lichtenberg-Kraag, B., Döring, F., Mandelkow, E. M., Biernat, J., Dorée, M., and Mandelkow, E. (1992) Mitogen-activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state, EMBO J. 11, 2131–2138.PubMedGoogle Scholar
  95. 91.
    Yang, S.-D., Song, J.-S., Yu, J. S., and Shiah, S.-G. (1993) Protein kinase Fa/GSK-3 phosphorylates i on Sen235-Pro and Sen424-Pro that are abnormally phosphorylated in Alzheimer’s disease brain, J. Neurochem. 61, 1742–1747.PubMedCrossRefGoogle Scholar
  96. 92.
    Scott, C. W., Spreen, R. C., Herman, J. L., Chow, F. P., Davison, M. D., Young, J., and Caputo, C. B. (1993) Phosphorylation of recombinant tau by cAMP-dependent protein kinase, J. Biol. Chem. 268, 1166–1173.PubMedGoogle Scholar
  97. 93.
    Steiner, B., Mandelkow, E. M., Biernat, J., Gustke, N., Meyer, H. E., Schmidt, B., Mieskes, G., Söling, H. D., Drechsel, D., Kirschner, M. W., Goedert, M., and Mandelkow, E. (1990) Phosphorylation of microtubule-associated protein tau: Identification of the site for Cat+/ calmodulin-dependent kinase and relationship with tau phosphorylation in Alzheimer tangles, EMBO J. 9, 3539–3544.PubMedGoogle Scholar
  98. 94.
    Mawal-Dewan, M., Henley, J., Van de Voorde, A., Trojanowski, J. Q., and Lee, V. M.-Y. (1994) The phosphorylation state of tau in the developing brain is regulated by phosphoprotein phosphatases, J. Biol. Chem. 269, 30981–30987.PubMedGoogle Scholar
  99. 95.
    Trojanowski, J. Q. and Lee, V. M.-Y. (1995) Phosphorylation of paired helical filament tau in Alzheimer’s disease neurofibrillary lesions: focusing on phosphatases, FASEB J. 9, 1570–1576.PubMedGoogle Scholar
  100. 96.
    Vandermeeren, M., Mercken, M., Vanmechelen, E., Six, J., Van de Voorde, A., Martin, J. J., and Cras, P. (1993) 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.PubMedCrossRefGoogle Scholar
  101. 97.
    Hock, C., Golombowski, S., Naser, W., and Mueller-Spahn, F. (1995) Increased levels of tau in cerebrospinal fluid of patients with Alzheimer’s disease—correlation with degree of cognitive impairment, Ann. Neurol. 183, 43–45.Google Scholar
  102. 98.
    Jensen, M., Basum, H., and Lannfelt, L. (1995) Increased cerebrospinal fluid tau in patients with Alzheimer’s disease, Neurosci. Lett. 186, 189–191.PubMedCrossRefGoogle Scholar
  103. 99.
    Mori, H., Hosoda, K., Matsubara, E., Nakamoto, T., Furiya,Y., Endoh, R., Usami, M., Shoji, M., and Maruyama, S. (1995) Tau in cerebrospinal fluid: establishment of the sandwich ELISA with antibody specific to the repeat sequence in tau, Neurosci. Lett. 186, 181–183.Google Scholar
  104. 100.
    Vigo-Pelfrey, C., Seubert, P., Barbour, R., Blomquist, C., Lee, M., Lee, D., Coria, F., Chang, L., Miller, B., Lieberburg, I., and Schenk, D. (1995) Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer’s disease, Neurology 45, 788–793.Google Scholar
  105. 101.
    Arai, H., Terajima, M., Miura, M., Higuchi, S., Muramatsu, T., Machida, N., Seki, H., Takase, S., Clark, C. M., Lee, V. M.-Y., Trojanowski, J. Q., and Sasaki, H. (1995) Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer’s disease, Ann. Neurol. 38, 649–652.PubMedCrossRefGoogle Scholar
  106. 102.
    Braak, E., Braak, H., and Mandelkow, E. M. (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads, Acta Neuropathol. 87, 554–567.PubMedCrossRefGoogle Scholar
  107. 103.
    Strittmatter, W. J., Saunders, A. M., Goedert, M., Weisgraber, K. H., Dong, L.-M., Jakes, R., Huang, D. Y., Pericak-Vance, M., Schmechel, D., and Roses, A. D. (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: Implications for Alzheimer disease, Proc. Natl. Acad. Sci. 91, 11183–11186.PubMedCrossRefGoogle Scholar
  108. 104.
    Lovestone, S., Reynolds, C. H., Latimer, D., Davis, D. R., Anderton, B. H., Gallo, J. M., Hanger, D., Mulot, S., Marquardt, B., Stabel, S., Woodgett, J. R., and Miller, C. C. J. (1994) Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells, Curr. Biol. 4, 1077–1086.PubMedCrossRefGoogle Scholar
  109. 105.
    Sperber, B. R., Leight, S., Goedert, M., and Lee, V. M.-Y. (1995) Glycogen synthase kinase-313 phosphorylates tau protein at multiple sites in intact cells, Neurosci. Lett. 197, 149–153.PubMedCrossRefGoogle Scholar
  110. 106.
    Götz, J., Probst, A., Spillantini, M. G., Schäfer, T., Jakes, R., Bürki, K., and Goedert, M. (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform, EMBO J. 14, 1304–1313.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Michel Goedert
  • John Q. Trojanowski
  • Virginia M.-Y. Lee

There are no affiliations available

Personalised recommendations