NeuroMolecular Medicine

, Volume 2, Issue 2, pp 131–150

Tau and axonopathy in neurodegenerative disorders

  • Makoto Higuchi
  • Virginia M.-Y. Lee
  • John Q. Trojanowski


The microtubule (MT)-associated protein (MAP) tau in neurons has been implicated as a significant factor in the axonal growth, development of neuronal polarity, and the maintenance of MT dynamics. Tau is localized to the axon, and is known to promote MT assembly and to stabilize axonal MTs. These functions of tau are primarily regulated by the activities of protein kinases and phosphatases. In Alzheimer’s disease and other neurodegenerative disorders, abundant filamentous tau inclusions are found to be major neuropathological characteristics of these diseases. Both somato-dendritic and axonal tau lesions appear to be closely associated with axonal disruption. Furthermore, recent discoveries of pathogenic mutations on the tau gene suggest that abnormalities of tau alone are causative of neurodegeneration. Finally, analyses of transgenic mice that express human tau proteins have enabled in vivo quantitative assessments of axonal functions and have provided information about mechanistic relationships between pathological alteration of tau and axonal degeneration.

Index Entries

Tau axonal transport microtubules Alzheimer’s disease tauopathies 


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  1. Ahlijanian M. K., Barrezueta N. X., Williams R. D., Jakowski A., Kowsz K. P., et al. (2000) Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc. Natl. Acad. Sci. USA 97(6), 2910–2915.PubMedGoogle Scholar
  2. Andreadis A., Brown W. M., and Kosik K. S. (1992) Structure and novel exons of the human tau gene. Biochemistry 31(43), 10,626–10,633.Google Scholar
  3. Arrasate M., Perez M., Armas-Portela R., and Avila J. (1999) Polymerization of tau peptides into fibrillar structures. The effect of FTDP-17 mutations. FEBS Lett. 446(1), 199–202.PubMedGoogle Scholar
  4. Arriagada P. V., Growdon J. H., Hedley-Whyte E. T., and Hyman B. T. (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42(3 Pt 1), 631–639.PubMedGoogle Scholar
  5. Auer I. A., Schmidt M. L., Lee V. M.-Y., et al. (1995) Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer’s disease. Acta Neuropathol. (Berl) 90, 547–551.Google Scholar
  6. Baas P. W., Deitch J. S., Black M. M., and Banker G. A. (1988) Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc. Natl. Acad. Sci. USA 85(21), 8335–8339.PubMedGoogle Scholar
  7. Bancher C., Lassmann H., Budka H., et al. (1987) Neurofibrillary tangles in Alzheimer’s disease and progressive supranuclear palsy: antigenic similarities and differences. Micortubule-associated protein tau antigenicity is prominent in all types of tangles. Acta Neuropathol. (Berl) 74, 39–46.Google Scholar
  8. Bancher C., Brunner C., Lassmann H., Budka H., Jellinger K., Wiche G., et al. (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res. 477(1–2), 90–99.PubMedGoogle Scholar
  9. Bancher C., Braak H., Fischer P., and Jellinger K. A. (1993) Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer’s and Parkinson’s disease patients. Neurosci. Lett. 162(1–2), 179–182.PubMedGoogle Scholar
  10. Bancher C., Jellinger K., Lassmann H., Fischer P., and Leblhuber F. (1996) Correlations between mental state and quantitative neuropathology in the Vienna Longitudinal Study on Dementia. Eur. Arch. Psychiatry Clin. Neurosci. 246(3), 137–146.PubMedGoogle Scholar
  11. Barghorn S., Zheng-Fischhöfer Q., Ackmann M., Biernat J., von Bergen M., et al. (2000) Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 39(38), 11,714–11,721.Google Scholar
  12. Baudier J. and Cole R. D. (1987) Phosphorylation of tau proteins to a state like that in Alzheimer’s brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J. Biol. Chem. 262(36), 17,577–17,583.Google Scholar
  13. Baumann K., Mandelkow E. M., Biernat J., Piwnica-Worms H., and Mandelkow E. (1993) Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 336(3), 417–424.PubMedGoogle Scholar
  14. Bernhardt R. and Matus A. (1984) Light and electron microscopic studies of the distribution of microtubule-associated protein 2 in rat brain: a difference between dendritic and axonal cytoskeletons. J. Comp. Neurol. 226(2), 203–221.PubMedGoogle Scholar
  15. Biernat J., Gustke N., Drewes G., Mandelkow E. M., and Mandelkow E. (1993) Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immuno-reactivity and microtubule binding. Neuron 11(1), 153–163.PubMedGoogle Scholar
  16. Billingsley M. L. and Kincaid R. L. (1997) Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J. 323 (Pt 3), 577–591.PubMedGoogle Scholar
  17. Binder L. I., Frankfurter A., and Rebhun L. I. (1985) The distribution of tau in the mammalian central nervous system. J. Cell Biol. 101(4), 1371–1378.PubMedGoogle Scholar
  18. Bobinski M., Wegiel J., Tarnawski M., Bobinski M., Reisberg B., de Leon M. J., et al. (1997) Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease. J. Neuropathol. Exp. Neurol. 56(4), 414–420.PubMedGoogle Scholar
  19. Braak H. and Braak E. (1987) Argyrophilic grains: characteristic pathology of cerebral cortex in cases of adult onset dementia without Alzheimer changes. Neurosci. Lett. 76, 124–127.PubMedGoogle Scholar
  20. Braak H. and Braak E. (1992) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging 16(3), 271–278, discussion 278–284.Google Scholar
  21. 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. (Berl) 87(6), 554–567.Google Scholar
  22. Brady S. T., Witt A. S., Kirkpatrick L. L., de Waegh S. M., Readhead C., Tu P. H., et al. (1999) Formation of compact myelin is required for maturation of the axonal cytoskeleton. J. Neurosci. 19(17), 7278–7288.PubMedGoogle Scholar
  23. 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(6), 1089–1099.PubMedGoogle Scholar
  24. Brandt R., Leger J., and Lee G. (1995) Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J. Cell Biol. 131(5), 1327–1340.PubMedGoogle Scholar
  25. Brion J. P., Guilleminot J., Couchie D., Flament D. J., and Nunez J. (1988) Both adult and juvenile tau microtubule-associated proteins are axon specific in the developing and adult rat cerebellum. Neuroscience 25(1), 139–146.PubMedGoogle Scholar
  26. Brion J. P., Tremp G., and Octave J. N. (1999) Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer’s disease. Am. J. Pathol. 154(1), 255–270.PubMedGoogle Scholar
  27. Buée L., Bussiere T., Buee-Scherrer V., Delacourte A., and Hof P. R. (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Brain Res. Rev. 33(1), 95–130.PubMedGoogle Scholar
  28. Buée-Scherrer V., Buée L., Hof P. R., et al. (1995) Neurofibrillary degeneration in amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: immunochemical characterization of tau proteins. Am. J. Pathol. 146, 924–932.PubMedGoogle Scholar
  29. Bugiani O., Murrell J. R., Giaccone G., Hasegawa M., Ghigo G., et al. (1999) Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J. Neuropathol. Exp. Neurol. 58(6), 667–677.PubMedGoogle Scholar
  30. Burton P. R. and Paige J. L. (1981) Polarity of axoplasmic microtubules in the olfactory nerve of the frog. Proc. Natl. Acad. Sci. USA 78(5), 3269–3273.PubMedGoogle Scholar
  31. 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(3), 717–730.PubMedGoogle Scholar
  32. Caceres A. and Kosik K. S. (1990) Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 343(6257), 461–463.PubMedGoogle Scholar
  33. Caceres A., Potrebic S., and Kosik K. S. (1991) The effect of tau antisense oligonucleotides on neurite formation of cultured cerebellar macroneurons. J. Neurosci. 11(6), 1515–1123.PubMedGoogle Scholar
  34. Chen J., Kanai Y., Cowan N. J., and Hirokawa N. (1992) Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons. Nature 360(6405), 674–677.PubMedGoogle Scholar
  35. Chin S. S.-M. and Goldman J. E. (1996) Glial inclusions in CNS degenerative diseases. J. Neuropathol. Exp. Neurol. 55(5), 499–508.PubMedGoogle Scholar
  36. Clark L. N., Poorkaj P., Wszolek Z., Geschwind D. H., Nasreddine Z. S., et al. (1998) Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc. Natl. Acad. Sci. USA 95(22), 13,103–13,107.Google Scholar
  37. Cleveland D. W., Hwo S.-Y., and Kirschner M. W. (1977) Purification of tau, a microtubule-associated protein that induces assembly of micro-tubules from purified tubulin. J. Mol. Biol. 116(2), 207–225.PubMedGoogle Scholar
  38. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123), 921–923.PubMedGoogle Scholar
  39. Couchie D., Mavilia C., Georgieff I. S., Liem R. K., 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(10), 4378–4381.PubMedGoogle Scholar
  40. Cummings B. J. and Cotman C. W. (1995) Image analysis of beta-amyloid load in Alzheimer’s disease and relation to dementia severity. Lancet 346(8989), 1524–1528.PubMedGoogle Scholar
  41. Cummings B. J., Pike C. J., Shankle R., and Cotman C. W. (1996) Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer’s disease. Neurobiol. Aging 17(6), 921–933.PubMedGoogle Scholar
  42. Dawson H. N., Ferreira A., Eyster M. V., Ghoshal N., Binder L. I., and Vitek M. P. (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J. Cell Sci. 114(Pt 6), 1179–1187.PubMedGoogle Scholar
  43. De Camilli P., Miller P. E., Navone F., Theurkauf W. E., and Vallee R. B. (1984) Distribution of microtubule-associated protein 2 in the nervous system of the rat studied by immunofluorescence. Neuroscience 11(4), 817–846.PubMedGoogle Scholar
  44. de Waegh S. M., Lee V. M.-Y., and Brady S. T. (1992) Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell 68, 451–463.PubMedGoogle Scholar
  45. Dickson D. W., Crystal H. A., Mattiace L. A., Masur D. M., Blau A. D., Davies P., et al. (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol. Aging 13(1), 179–189.PubMedGoogle Scholar
  46. Dickson D. W., Feany M. B., Yen S. H., Mattiace L. A., and Davies P. (1996) Cytoskeletal pathology in non-Alzheimer degenerative dementia: new lesions in diffuse Lewy body disease, Pick’s disease, and corticobasal degeneration. J. Neural. Transm. Suppl. 47, 31–46.Google Scholar
  47. Dickson D. W. (1998) Pick’s disease: a modern approach. Brain Pathol. 8(2), 339–354.PubMedGoogle Scholar
  48. 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. Biol. Cell 3(10), 1141–1154.PubMedGoogle Scholar
  49. Drewes G., Lichtenberg-Kraag B., Doring F., Mandelkow E. M., Biernat J., Goris J., et al. (1992) Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 11(6), 2131–2138.PubMedGoogle Scholar
  50. Drewes G., Mandelkow E. M., Baumann K., Goris J., Merlevede W., and Mandelkow E. (1993) Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcineurin and phosphatase-2A. FEBS Lett. 336(3), 425–432.PubMedGoogle Scholar
  51. Drewes G., Ebneth A., Preuss U., Mandelkow E. M., and Mandelkow E. (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89(2), 297–308.PubMedGoogle Scholar
  52. D’Souza I., Poorkaj P., Hong M., Nochlin D., Lee V. M.-Y., et al. (1999) Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc. Natl. Acad. Sci. USA 96(10), 5598–5603.PubMedGoogle Scholar
  53. Duff K., Knight H., Refolo L. M., Sanders S., Yu X., Picciano M., et al. (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis. 7(2), 87–98.PubMedGoogle Scholar
  54. Feany M. B. and Dickson D. W. (1995) Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am. J. Pathol. 146(6), 1388–1396.PubMedGoogle Scholar
  55. Feany M. B., Mattiace L. A., and Dickson D. W. (1996) Neuropathologic overlap of progressive supra-nuclear palsy, Pick’s disease and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 55(1), 53–67.PubMedGoogle Scholar
  56. Flament S., Delacourte A., Verny M., et al. (1991) Abnormal tau proteins in progressive supranuclear palsy: similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol. (Berl) 81, 591–596.Google Scholar
  57. Forman M. S., Lee V. M.-Y., and Trojanowski J. Q. (2000) New insights into genetic and molecular mechanisms of brain degeneration in tauopathies. J. Chem. Neuroanat. 20(3–4), 225–244.PubMedGoogle Scholar
  58. Forman M. S., Zhukareva V., Bergeron C., Chin S. S., Grossman M., Clark C., et al. (2002) Signature tau neuropathology in gray and white matter of corticobasal degeneration. Am. J. Pathol. 160(6), 2045–2053.PubMedGoogle Scholar
  59. Foster N. L., Wilhelmsen K., Sima A. A., et al. (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference participants. Ann. Neurol. 41, 706–715.PubMedGoogle Scholar
  60. Gamblin T. C., King M. E., Dawson H., Vitek M. P., Kuret J., et al. (2000) In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants. Biochemistry 39(20), 6136–6144.PubMedGoogle Scholar
  61. Games D., Adams D., Alessandrini R., Barbour R., Berthelette P., et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373(6514), 523–527.PubMedGoogle Scholar
  62. Ginsberg S. D., Galvin J. E., Chiu T. S., Lee V. M.-Y., Masliah E., and Trojanowski J. Q. (1998) RNA sequestration to pathological lesions of neurodegenerative diseases. Acta Neuropathol. 96(5), 487–494.PubMedGoogle Scholar
  63. Goedert M., Wischik C. M., Crowther R. A., Walker J. E., and Klug A. (1988) Cloning and swquencing 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. USA 85(11), 4051–4055.PubMedGoogle Scholar
  64. 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(4), 519–526.PubMedGoogle Scholar
  65. 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. EMBO J. 9(13), 4225–4230.PubMedGoogle Scholar
  66. Goedert M., Cohen E. S., Jakes R., and Cohen P. (1992a) p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer’s disease. FEBS Lett. 312(1), 95–99.PubMedGoogle Scholar
  67. Goedert M., Spillantini M. G., Cairns N. J., and Crowther R. A. (1992b) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8(1), 159–168.PubMedGoogle Scholar
  68. Goedert M., Jakes R., Crowther R. A., Six J., Lubke U., Vandermeeren M., et al. (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc. Natl. Acad. Sci. USA 90(11), 5066–5070.PubMedGoogle Scholar
  69. Goedert M., Spillantini M.G., Jakes R., Crowther R. A., Vanmechelen E., Probst A., et al. (1995) Molecular dissection of the paired helical filament. Neurobiol. Aging 16(3), 325–334.PubMedGoogle Scholar
  70. Goedert M., Jakes R., Spillantini M. G., Hasegawa M., Smith M. J., and Crowther R. A. (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induce by sulphated glycosaminoglycans. Nature 383(6600), 550–553.PubMedGoogle Scholar
  71. Goedert M., Hasegawa M., Jakes R., Lawler S., Cuenda A., and Cohen P. (1997a) Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett. 409(1), 57–62.PubMedGoogle Scholar
  72. Goedert M., Trojanowski J. Q., and Lee V.M.-Y. (1997b) The neurofibrillary pathology of Alzheimer’s disease, in The Molecular and Genetic Basis of Neurological Diseases, second ed. (Prusiner S. B., Rosenberg R. N., Di Mauro S., et al., eds.), Boston, MA, pp. 613–627.Google Scholar
  73. Goedert M., Jakes R., and Crowther R. A. (1999) Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments. FEBS Lett. 450(3), 306–311.PubMedGoogle Scholar
  74. Gomez-Isla T., Price J. L., McKeel D. W. Jr., Morris J. C., Growdon J. H., and Hyman B. T. (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci. 16(14), 4491–4500.PubMedGoogle Scholar
  75. Goode B. L. and Feinstein S. C. (1994) Identification of a novel microtubule binding and assembly domain in the developmentally regulated interrepeat region of tau. J. Cell Biol. 124(5), 769–782.PubMedGoogle Scholar
  76. Götz J., Probst A., Spillantini M. G., Schafer T., Jakes R., et al. (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14(7), 1304–1313.PubMedGoogle Scholar
  77. Götz J., Chen F., van Dorpe J., and Nitsch R. M. (2001) Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta 42 fibrils. Science 293(5534), 1491–1495.PubMedGoogle Scholar
  78. 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(15), 5827–5831.PubMedGoogle Scholar
  79. 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(1), 564–569.PubMedGoogle Scholar
  80. Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., and Binder L. I. (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA 83(13), 4913–4917.PubMedGoogle Scholar
  81. Gustke N., Steiner B., Mandelkow E. M., Biernat J., Meyer H. E., Goedert M., et al. (1992) The Alzheimer-like phosphorylation of tau protein reduces microtubule binding and involves Ser-Pro and Thr-Pro motifs. FEBS Lett. 307(2), 199–205.PubMedGoogle Scholar
  82. Hagestedt T., Lichtenberg B., Wille H., Mandelkow E. M., and Mandelkow E. (1989) Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation. J. Cell Biol. 109(4 Pt 1), 1643–1651.PubMedGoogle Scholar
  83. Hanger D. P., Hughes K., Woodgett J. R., Brion J. P., 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 localisation of the kinase. Neurosci. Lett. 147(1), 58–62.PubMedGoogle Scholar
  84. Harada A., Oguchi K., Okabe S., Kuno J., Terada S., Ohshima T., et al. (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369(6480), 488–491.PubMedGoogle Scholar
  85. Harris K. A., Oyler G. A., Doolittle G. M., Vincent I., Lehman R. A., Kincaid R. L., et al. (1993) Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. Ann. Neurol. 33(1), 77–87.PubMedGoogle Scholar
  86. 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(1), 25–30.PubMedGoogle Scholar
  87. Hasegawa M., Crowther R. A., Jakes R., and Goedert M. (1997) Alzheimer-like changes in microtubule-associated protein tau induced by sulfated glycosaminoglycans. Inhibition of microtubule binding, stimulation of phosphorylation, and filament assembly depend on the degree of sulfation. J. Biol. Chem. 272(52), 33,118–33,124.Google Scholar
  88. Hasegawa M., Smith M. J., and Goedert M. (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 437(3), 207–210.PubMedGoogle Scholar
  89. Hasegawa M., Smith M. J., Iijima M., Tabira T., and Goedert M. (1999) FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10. FEBS Lett. 443(2), 93–96.PubMedGoogle Scholar
  90. Hauw J. J., Daniel S. E., Dickson D., Horoupian D. S., Jellinger K., et al. (1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44(11), 2015–2019.PubMedGoogle Scholar
  91. Heidemann S. R., Landers J. M., and Hamborg M. A. (1981) Polarity orientation of axonal microtubules. J. Cell Biol. 91(3 Pt 1), 661–665.PubMedGoogle Scholar
  92. Higuchi M., Trojanowski J. Q., and Lee V. M.-Y. (2002) Tau protein and tauopathy, in Neuropsychopharmacology: The Fifth Generation of Progress (Davis K. L., Charney D., Coyle J., and Nemeroff C. N., eds.), Lippincott Williams & Wilkins, Baltimore, MD, pp. 1339–1353.Google Scholar
  93. Himmler A., Drechsel D., Kirschner M. W., and Martin D. W. Jr. (1989) Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol. Cell Biol. 9(4), 1381–1388.PubMedGoogle Scholar
  94. Hirano A., Malamud N., and Kurland L. T. (1961) Parkinsonism dementia complex in endemic disease on the island of Guam—pathologic features. Brain 84, 662.PubMedGoogle Scholar
  95. Hirokawa N., Funakoshi T., Sato-Harada R., and Kanai Y. (1996) Selective stabilization of tau in axons and microtubule-associated protein 2C in cell bodies and dendrites contributes to polarized localization of cytoskeletal proteins in mature neurons. J. Cell Biol. 132(4), 667–679.PubMedGoogle Scholar
  96. Hof P. R., Nimchinsky E. A., Buée-Scherrer V., et al. (1994) Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders. Acta Neuropathol. (Berl) 88, 397–404.Google Scholar
  97. Hoffmann R., Lee V. M.-Y., Leight S., Varga I., and Otvos L. Jr. (1997) Unique Alzheimer’s disease paired helical filament specific epitopes involve double phosphorylation at specific sites. Biochemistry 36(26), 8114–8124.PubMedGoogle Scholar
  98. Hong M. and Lee V. M.-Y. (1997) Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J. Biol. Chem. 272(31), 19,547–19,553.Google Scholar
  99. Hong M., Chen D. C., Klein P.S., and Lee V.M.-Y. (1997) Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J. Biol. Chem. 272(40), 25,326–25,332.Google Scholar
  100. Hong M., Zhukareva V., Vogelsberg-Ragaglia V., Wszolek Z., Reed L., Miller B. I., et al. (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282(5395), 1914–1917.PubMedGoogle Scholar
  101. Hosoi T., Uchiyama M., Okumura E., Saito T., Ishiguro K., Uchida T., et al. (1995) Evidence for cdk5 as a major activity phosphorylating tau protein in porcine brain extract. J. Biochem. (Tokyo) 117(4), 741–749.Google Scholar
  102. Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., et al. (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274(5284), 99–102.PubMedGoogle Scholar
  103. Hutton M., Lendon C. I., Rizzu P., Baker M., Froelich S., et al. (1998) Association of missense and 5′-spilice-site mutations in tau with the inherited dementia FTDP-17. Nature 393(6686), 702–705.PubMedGoogle Scholar
  104. Hyman B. T., West H. L., Gomez-Isla T., and Mui S. (1995) Quantitative neuropathology in Alzheimer’s disease: Neuronal loss in high-order association cortex parallels dementia. In Research Advances in Alzheimer’s Disease and Related Disorders (Iqbal K., Mortimer J. A., Winblad B., and Wisniewski H. M., eds.), Wiley, New York, NY, pp. 453–460.Google Scholar
  105. Iijima M., Tabira T., Poorkaj P., Schellenberg G. D., Trojanowski J. Q., et al. (1999) A distinct familial presenile dementia with a novel missense mutation in the tau gene. NeuroReport 10(3), 497–501.PubMedGoogle Scholar
  106. Ikegami S., Harada A., and Hirokawa N. (2000) Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett. 279(3), 129–132.PubMedGoogle Scholar
  107. Ishiguro K., Takamatsu M., Tomizawa K., Omori A., Takahashi M., Arioka M., Uchida T., and Imahori K. (1992) Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J. Biol. Chem. 267(15), 10,897–10,901.Google Scholar
  108. Ishihara T., Hong M., Zhang B., Nakagawa Y., Lee M. K., et al. (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24(3), 751–762.PubMedGoogle Scholar
  109. Ishihara T., Zhang B., Higuchi M., Yashiyama Y., Trojanowski J. Q., and Lee V. M.-Y. (2001) Age dependent induction of congophilic neurofibrillary inclusions in tau transgenic mice. Am. J. Pathol. 158(2), 555–562.PubMedGoogle Scholar
  110. Ishihara T., Higuchi M., Zhang B., Yoshiyama Y., Hong M., Trojanowski J. Q., et al. (2001) Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J. Neurosci. 21(16), 6026–6035.PubMedGoogle Scholar
  111. Itagaki S., McGeer P. L., Akiyama H., et al. (1989) A case of adult-onset dementia with argyrophilic grains. Ann. Neurol. 26, 685–689.PubMedGoogle Scholar
  112. Iwatsubo T., Hasegawa M., and Ihara Y. (1994) Neuronal and glial tau-positive inclusions in diverse neurologic diseases share common phosphorylation characteristics. Acta Neuropathol. 88(2), 129–136.PubMedGoogle Scholar
  113. Kampers T., Friedhoff P., Biernat J., Mandelkow E. M., and Mandelkow E. (1996) RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399(3), 344–349.PubMedGoogle Scholar
  114. Kanemaru K., Takio K., Miura R., Titani K., and Ihara Y. (1992) Fetal-type phosphorylation of the tau in paired helical filaments. J. Neurochem. 58(5), 1667–1675.PubMedGoogle Scholar
  115. Kidd M. (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197, 192–194.PubMedGoogle Scholar
  116. Kirkpatrick L. L., Witt A. S., Payne H. R., Shine H. D., and Brady S. T. (2001) Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons. J. Neurosci. 21(7), 2288–2297.PubMedGoogle Scholar
  117. Kobayashi S., Ishiguro K., Omori A., Takamatsu M., Arioka M., Imahori K., et al. (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 microtubule. FEBS Lett. 335(2), 171–175.PubMedGoogle Scholar
  118. Komori T., Arai N., Oda M., Nakayama H., Mori H., Yagishita S., et al. (1998) Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. (Berl) 96(4), 401–408.Google Scholar
  119. Komori T. (1999) Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol. 9(4), 663–679.PubMedGoogle Scholar
  120. Kondo J., Honda T., Mori H., Hamada Y., Miura R., Ogawara M., et al. (1988) The carboxyl third of tau is tightly bound to paired helical filaments. Neuron 1(9), 827–834.PubMedGoogle Scholar
  121. Kosik K. S., Orecchio L. D., Binder L., Trojanowski J. Q., Lee V. M.-Y., and Lee G. (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1(9), 817–825.PubMedGoogle Scholar
  122. Kosik K. S., Orecchio L. D., Bakalis S., and Neve R. L. (1989) Developmentally regulated expression of specific tau sequences. Neuron 2(4), 1389–1397.PubMedGoogle Scholar
  123. Kowall N. W. and Kosik K. S. (1987) Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer’s disease. Ann. Neurol. 22(5), 639–643.PubMedGoogle Scholar
  124. Ksiezak-Reding H., Morgan K., Mattiace L. A., et al. (1994) Ultrastructure and biochemical composition of paired helical filaments in corticobasal degeneration. Am. J. Pathol. 145, 1496–1508.PubMedGoogle Scholar
  125. Lee G., Cowan N., and Kirschner M. W. (1988) The primary structure and heterogeneity of tau protein from mouse brain. Science 239(4837), 285–288.PubMedGoogle Scholar
  126. Lee G., Neve R. L., and Kosik K. S. (1989) The microtubule binding domain of tau protein. Neuron 2(6), 1615–1624.PubMedGoogle Scholar
  127. Lee V. M.-Y., Balin B. J., Otvos L. Jr., and Trojanowski J. Q. (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251(4994), 675–678.PubMedGoogle Scholar
  128. Lee V. M.-Y., Goedert M., and Trojanowski J. Q. (2001) Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159.PubMedGoogle Scholar
  129. Leost M., Schultz C., Link A., Wu Y. Z., Biernat J., Mandelkow E. M., et al. (2000) Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur. J. Biochem. 267(19), 5983–5994.PubMedGoogle Scholar
  130. Lewis J., McGowan E., Rockwood J., Melrose H., Nacharaju P., et al. (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25(4), 402–405.PubMedGoogle Scholar
  131. Lewis J., Dickson D. W., Lin W. L., Chisholm L., Corral A., Jones G., et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293(5534), 1487–1491.PubMedGoogle Scholar
  132. Lieberman A. P., Trojanowski J. Q., Lee V. M.-Y., et al. (1998) Cognitive, neuroimaging, and pathological studies in a patient with Pick’s disease. Ann. Neurol. 43, 259–265.PubMedGoogle Scholar
  133. Lindwall G. and Cole R. D. (19??) Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259(8), 5301–5305.Google Scholar
  134. Litersky J. M. and Johnson G. V. (1992) Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. J. Biol. Chem. 267(3), 1563–1568.PubMedGoogle Scholar
  135. Litman P., Barg J., Rindzoonski L., and Ginzburg I. (1993) Subcellular localization of tau mRNA in differentiating neuronal cell culture: implications for neuronal polarity. Neuron 10(4), 627–638.PubMedGoogle Scholar
  136. Litvan I., Agid Y., Calne D., Campbell G., Dubois B., et al. (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47(1), 1–9.PubMedGoogle Scholar
  137. LoPresti P., Szuchet S., Papasozomenos S. C., Zinkowski R. P., and Binder L. I. (1995) Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc. Natl. Acad. Sci. USA 92(22), 10,369–10,373.Google Scholar
  138. Love S., Bridges L. R., and Case C. P. (1995) Neurofibrillary tangles in Niemann-Pick disease type C. Brain 188, 119–129.Google Scholar
  139. Lovell M. A., Ehmann W. D., Mattson M. P., and Markesbery W. R. (1997) Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease. Neurobiol. Aging 18, 457–461.PubMedGoogle Scholar
  140. Lovestone S., Hartley C. L., Pearce J., and Anderton B. H. (1996) Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules. Neuroscience 73(4), 1145–1157.PubMedGoogle Scholar
  141. Lovestone S., Davis D. R., Webster M. T., Kaech S., Brion J. P., Matus A., et al. (1999) Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol. Psychiatry 45(8), 995–1003.PubMedGoogle Scholar
  142. Mandelkow E. M., Drewes G., Biernat J., Gustke N., Van Lint J., Vandenheede J. R., et al. (1992) Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 314(3), 315–321.PubMedGoogle Scholar
  143. Matsumoto S., Hirano A., and Goto S. (1990) Spinal cord neurofibrillary tangles of Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia complex: an immunohistochemical study. Neurology 40, 975–979.PubMedGoogle Scholar
  144. Matsuo E. S., Shin R. W., Billingsley M. L., Van deVoorde A., O’Connor M., Trojanowski J. Q., et al. (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(4), 989–1002.PubMedGoogle Scholar
  145. Mattson M. P. (1990) Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron 4, 105–117.PubMedGoogle Scholar
  146. Mattson M. P. (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77, 1081–1132.PubMedGoogle Scholar
  147. Mattson M. P., Fu W., Waeg G., and Uchida K. (1997) 4-Hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau. Neuroreport 8, 2275–2281.PubMedGoogle Scholar
  148. 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 rat brain is regulated by phosphoprotein phosphatases. J. Biol. Chem. 269(49), 30,981–30,987.Google Scholar
  149. Mawal-Dewan M., Schmidt M. L., Balin B., Perl D. P., Lee V. M.-Y., and Trojanowski J. Q. (1996) Identification of phosphorylation sites in PHF-TAU from patients with Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex. J. Neuropathol. Exp. Neurol. 55(10), 1051–1059.PubMedGoogle Scholar
  150. McKee A. C., Kosik K. S., and Kowall N. W. (1991) Neuritic pathology and dementia in Alzheimer’s disease. Ann. Neurol. 30(2), 156–165.PubMedGoogle Scholar
  151. McKhann G. M., Albert M. S., Grossman M., Miller B., Dickson D., and Trojanowski J. Q. (2001) Work Group on Frontotemporal Dementia and Pick’s Disease. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch. Neurol. 58(11), 1803–1809.PubMedGoogle Scholar
  152. McQuaid S., Allen I. V., McMahon J., and Kirk J. (1994) Association of measles virus with neurofibrillary tangles in subacute sclerosing panencephalitis: a combined in situ hybridization and immunocytochemical investigation. Neuropathol. Appl. Neurobiol. 20, 103–110.PubMedGoogle Scholar
  153. Mercken M., Fischer I., Kosik K. S., and Nixon R. A. (1995) Three distinct axonal transport rates for tau, tubulin, and other microtubule-associated proteins: evidence for dynamic interactions of tau with microtubules in vivo. J. Neurosci. 15(12), 8259–8267.PubMedGoogle Scholar
  154. Mercken M., Grynspan F., and Nixon R. A. (1995) Differential sensitivity to proteolysis by brain calpain of adult human tau, fetal human tau and PHF-tau. FEBS Lett. 368(1), 10–14.PubMedGoogle Scholar
  155. Merrick S. E., Trojanowski J. Q., and Lee V. M.-Y. (1997) Selective destruction of stable microtubules and axons by inhibitors of protein serine/threonine phosphatases in cultured human neurons. J. Neurosci. 17(15), 5726–5737.PubMedGoogle Scholar
  156. Montine K. S., Reich E., Neely M. D., Sidell K. R., Olson S. J., Markesbery W. R., et al. (1998) Distribution of reducible 4-hydroxynonenal adduct immunoreactivity in Alzheimer disease is associated with APOE genotype. J. Neuropathol. Exp. Neurol. 57, 415–425.PubMedGoogle Scholar
  157. Mori H., Nishimura M., Namba Y., and Oda M. (1994) Corticobasal degeneration: a disease with widespread appearance of abnormal tau and neurofibrillary tangles, and its relation to progressive supranuclear palsy. Acta Neuropathol. (Berl) 88, 113–121.Google Scholar
  158. Morishima-Kawashima M., Hasegawa M., Takio K., Suzuki M., Yoshida H., Titani K., et al. (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau. J. Biol. Chem. 270(2), 823–829.PubMedGoogle Scholar
  159. Munoz-Montano J. R., Moreno F. J., Avila J., and Diaz-Nido J. (1997) Lithium inhibits Alzheimer’s disease-like tau protein phosphorylation in neurons. FEBS Lett. 411(2–3), 183–188.PubMedGoogle Scholar
  160. Murayama S., Mori H., Ihara Y., and Tomonaga M. (1990) Immunocytochemical and ultrastructural studies of Pick’s disease. Ann. Neurol. 27, 394–405.PubMedGoogle Scholar
  161. Murrell J. R., Spillantini M. G., Zolo P., Guazzelli M., Smith M. J., et al. (1999) Tau gene mutation G389R causes a tauopathy with abundant Pick body-like inclusions and axonal deposits. J. Neuropathol. Exp. Neurol. 58(12), 1207–1226.PubMedGoogle Scholar
  162. Nacharaju P., Lewis J., Easson C., Yen S., Hackett J., et al. (1999) Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett. 447(2–3), 195–199.PubMedGoogle Scholar
  163. Nadelhaft I. (1974) Microtubule densities and total numbers in selected axons of the crayfish abdominal nerve cord. J. Neurocytol. 3(1), 73–86.PubMedGoogle Scholar
  164. Neve R. L., Harris P., Kosik K. S., Kurmit D. M., and Donlon T. A. (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res. 387(3), 271–280.PubMedGoogle Scholar
  165. Neve R. L. and Robakis N. K. (1998) Alzheimer’s disease: a re-examination of the amyloid hypothesis. Trends Neurosci. 21(1), 15–19.PubMedGoogle Scholar
  166. Nishimura M., Namba Y., Ikeda K., and Oda M. (1992) Glial fibrillary tangles with straight tubules in the brains of patients with progressive supranuclear palsy. Neurosci. Lett. 143(1–2), 35–38.PubMedGoogle Scholar
  167. Okabe S. and Hirokawa N. (1989) Rapid turnover of microtubule-associated protein MAP2 in the axon revealed by microinjection of biotinylated MAP2 into cultured neurons. Proc. Natl. Acad. Sci. USA 86(11), 4127–4131.PubMedGoogle Scholar
  168. Patrick G. N., Zukerberg L., Nikolic M., de la Monte S., Dikkes P., and Tsai L. H. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402(6762), 615–622.PubMedGoogle Scholar
  169. Paulus W. and Selim M. (1990) Corticonigral degeneration with neuronal achromasia and basal neurofibrillary tangles. Acta Neuropathol. (Berl) 81, 89–94.Google Scholar
  170. Perez M., Valpuesta J. M., Medina M., Montejo G., and Avila J. (1996) Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. J. Neurochem. 67(3), 1183–1190.PubMedGoogle Scholar
  171. Perry G., Stwart D., Friedman R., et al. (1987) Filaments of Pick’s bodies contain altered cytoskeletal elements. Am. J. Pathol. 127, 559–568.PubMedGoogle Scholar
  172. Pickering-Brown S., Baker M., Yen S. H., Liu W. K., Hasegawa M., et al. (2000) Pick’s disease is associated with mutations in the tau gene. Ann. Neurol. 48(5), 806–808.Google Scholar
  173. Pollock N. J., Mirra S. S., Binder L. I., Hansen L. A., and Wood J. G. (1986) Filamentous aggregates in Pick’s disease, progressive supranuclear palsy, and Alzheimer’s disease share antigenic determinants with microtubule-associated protein, tau. Lancet 2(8517), 1211.PubMedGoogle Scholar
  174. Poorkaj P., Bird T. D., Wijsman E., Nemens E., Garruto R. M., et al. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43(6), 815–825.PubMedGoogle Scholar
  175. Probst A., Tolnay M., Langui D., Goedert M., and Spillantini M. G. (1996) Pick’s disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol. (Berl) 92, 588–596.Google Scholar
  176. Probst A., Götz J., Wiederhold K. H., Tolnay M., Mistl C., et al. (2000) Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. 99(5), 469–481.PubMedGoogle Scholar
  177. Reiderer B. and Matus A. (1985) Differential expression of distinct microtubule-associated proteins during brain development. Proc. Natl. Acad. Sci. USA 82(17), 6006–6009.Google Scholar
  178. Reynolds C. H., Utton M. A., Gibb G. M., Yates A., and Anderton B. H. (1997) Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J. Neurochem. 68(4), 1736–1744.PubMedGoogle Scholar
  179. Rizzini C., Goedert M., Hodges J. R., Smith M. J., Jakes R., et al. (2000) Tau gene mutation K257T causes a tauopathy similar to Pick’s disease. J. Neuropathol. Exp. Neurol. 59(11), 990–1001.PubMedGoogle Scholar
  180. Rizzu P., Van Swieten J. C., Joosse M., Hasegawa M., Stevens M., et al. (1999) High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am. J. Hum. Genet. 64(2), 414–421.PubMedGoogle Scholar
  181. Schmidt M. L., Huang R., Martin J. A., et al. (1996) Neurofibrillary tangles in progressive supranuclear palsy contain the same tau epitopes identified in Alzheimer’s disease PHF-tau. J. Neuropathol. Exp. Neurol. 55, 534–539.PubMedGoogle Scholar
  182. Schmidt M. L., Zhukareva V., Perl D. P., Sheridan S. K., Schuck T., Lee V. M.-Y., et al. (2001) Spinal cord neurofibrillary pathology in Alzheimer disease and Guam Parkinsonism-dementia complex. J. Neuropathol. Exp. Neurol. 60(11), 1075–1086.PubMedGoogle Scholar
  183. Schneider A., Biernat J., von Bergen M., Mandelkow E., and Mandelkow E. M. (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38(12), 3549–3558.PubMedGoogle Scholar
  184. Shankar S. K., Yanagihara R., Garruto R. M., Grundke-Iqbal I., Kosik K. S., and Gajdusek D. C. (1989) Immunocytochemical characterization of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Ann. Neurol. 25, 146–151.PubMedGoogle Scholar
  185. Shin R. W., Iwaki T., Kitamoto T., and Tateishi J. (1991) Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and alzheimer’s disease brain tissues. Lab. Investig. 64(5), 693–702.PubMedGoogle Scholar
  186. Snow A. D., Mar H., Nochlin D., Sekiguchi R. T., Kimata K., Koike Y., et al. (1990) Early accumulation of heparin sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer’s disease and Down’s syndrome. Am. J. Pathol. 137(5), 1253–1270.PubMedGoogle Scholar
  187. Sontag E., Nunbhakdi-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(6), 1131–1144.PubMedGoogle Scholar
  188. Sontag E., Nunbhakdi-Craig V., Lee G., Bloom G. S., and Mumby M. C. (1996) Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron 17(6), 1201–1207.PubMedGoogle Scholar
  189. Spillantini M. G., Murrell J. R., Goedert M., Farlow M. R., Klug A., and Ghetti B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95(13), 7737–7741.PubMedGoogle Scholar
  190. Spillantini M. G., Yoshida H., Rizzini C., Lantos P. L., Khan N., et al. (2000) A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann. Neurol. 48(6), 939–943.PubMedGoogle Scholar
  191. Spittaels K., Van den Haute C., Van Dorpe J., Bruynseels K., Vandezande K., et al. (1999) Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155(6), 2153–2165.PubMedGoogle Scholar
  192. Spittaels K., Van den Haute C., Van Dorpe J., Geerts H., Mercken M., Bruynseels K., et al. (2000) Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J. Biol. Chem. 275(52), 41,340–41,349.Google Scholar
  193. Stamer K., Vogel R., Thies E., Mandelkow E., and Mandelkow E. M. (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156(6), 1051–1063.PubMedGoogle Scholar
  194. Stanford P. M., Halliday G. M., Brooks W. S., Kwok J. B., Storey C. E., et al. (2000) Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations. Brain 123(5), 880–893.PubMedGoogle Scholar
  195. Stein-Behrens B., Mattson M. P., Chang I., Yeh M., and Sapolsky R. (1994) Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus. J. Neurosci. 14, 5373–5380.PubMedGoogle Scholar
  196. Strittmatter W. J., Saunders A. M., Goedert M., Weisgraber K. H., Dong L. M., Jakes R, et al. (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc. Natl. Acad. Sci. USA 91(23), 11,183–11,186.Google Scholar
  197. Sturchler-Pierrat C., Abramowski D., Duke M., Wiederhold K. H., Mistl C., et al. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 94(24), 13,287–13,292.Google Scholar
  198. Suzuki K., Parker C. C., Pentchev P. G., et al. Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol. (Berl) 89, 227–238.Google Scholar
  199. Takahashi M., Yasutake K., and Tomizawa K. (1999) Lithium inhibits neurite growth and tau protein kinase I/glycogen synthase kinase-3beta-dependent phosphorylation of juvenile tau in cultured hippocampal neurons. J. Neurochem. 73(5), 2073–2083.PubMedGoogle Scholar
  200. Takei Y., Teng J., Harada A., and Hirokawa N. (2000) Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J. Cell Biol. 150(5), 989–1000.PubMedGoogle Scholar
  201. Tanemura K., Murayama M., Akagi T., Hashikawa T., Tominaga T., Ichikawa M., et al. (2002) Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J. Neurosci. 22(1), 133–141.PubMedGoogle Scholar
  202. Tesseur I., Van Dorpe J., Bruynseels K., Bronfman F., Sciot R., Van Lommel A., et al. (2000) Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am. J. Pathol. 157(5), 1495–1510.PubMedGoogle Scholar
  203. Thal D. R., Arendt T., Waldmann G., Holzer M., Zedlick D., Rub U., et al. (1998) Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer’s disease is different from plaque and cortical microglial pathology. Neurobiol. Aging 19(6), 517–525.PubMedGoogle Scholar
  204. Thal D. R., Holzer M., Rub U., Waldmann G., Gunzel S., Zedlick D., et al. (2000) Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Exp. Neurol. 163(1), 98–110.PubMedGoogle Scholar
  205. Trinczek B., Biernat J., Baumann K., Mandelkow E. M., and Mandelkow E. (1995) Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules. Mol. Biol. Cell 6(12), 1887–1902.PubMedGoogle Scholar
  206. Trojanowski J. Q., Schuck T., Schmidt M. L., and Lee V. M.-Y. (1989) Distribution of tau proteins in the normal human central and peripheral nervous system. J. Histochem. Cytochem. 37(2), 209–215.PubMedGoogle Scholar
  207. Trojanowski J. Q., Schuck T., Schmidt M. L., and Lee V. M.-Y. (1989) Distribution of phosphate-independent MAP2 epitopes revealed with monoclonal antibodies in microwave-denatured human nervous system tissues. J. Neurosci. Methods 29(2), 171–180.PubMedGoogle Scholar
  208. Tsai L. H., Delalle I., Caviness V. S. Jr., Chae T., and Harlow E. (19??) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371(6496), 419–423.Google Scholar
  209. Umahara T., Hirano A., Kato S., et al. (1994) Demonstration of neurofibrillary tangles and neuropil thread-like structures in spinal cord white matter in parkinsonism-dementia complex on Guam and in Guamanian amyotrophic lateral sclerosis. Acta Neuropathol. (Berl) 88, 180–184.Google Scholar
  210. Verbeek M. M., Otte-Holler I., van den Born J., van den Heuvel L. P., David G., Wesseling P., et al. (1999) Agrin is major heparin sulfate proteoglycan accumulating in Alzheimer’s disease brain. Am. J. Pathol. 155(6), 2115–2125.PubMedGoogle Scholar
  211. Viereck C., Tucker R. P., Binder L. I., and Matus A. (1990) Phylogenetic conservation of brain microtubule-associated proteins MAP2 and tau. Neuroscience 26(3), 893–904.Google Scholar
  212. Vogelsberg-Ragaglia V., Bruce J., Richter-Lansberg C., Zhang B., Hong M., et al. (2000) Distinct FTDP-17 missense mutations in tau produce tau aggregates and other phathological phenotypes in transfected CHO cells. Mol. Biol. Cell 11(12), 4093–4104.PubMedGoogle Scholar
  213. Vogelsberg-Ragaglia V., Schuck T., Trojanowski J. Q., and Lee V. M.-Y. (2001) PP2A mRNA expression is quantitatively decreased in Alzheimer’s disease hippocampus. Exp. Neurol. 168(2), 402–412.PubMedGoogle Scholar
  214. Wakabayashi K., Oyanagi K., Makifuchi T., et al. (1994) Corticobasal degeneration: etiopathological significance of the cytoskeletal alterations. Acta Neuropathol. (Berl) 87, 545–553.Google Scholar
  215. Watanabe A., Hasegawa M., Suzuki M., Takio K., Morishima-Kawashima M., Titani K., et al. (1993) In vivo phosphorylation sites in fetal and adult rat tau. J. Biol. Chem. 268(34), 25,712–25,717.Google Scholar
  216. Weingarten M. D., Lockwood A. H., Hwo S. Y., and Kirschner M. W. (1975) A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA 72(5), 1858–1862.PubMedGoogle Scholar
  217. Wilhelmsen K. C., Lynch T., Pavlou E., et al. (1994) Localization of disnhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22. Am. J. Hum. Gen. 55, 1159–1165.Google Scholar
  218. Wilson D. M. and Binder L. I. (1997) Free fatty acids simulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. Am. J. Pathol. 150(6), 2181–2195.PubMedGoogle Scholar
  219. Wischik C. M., Novak M., Thogersen H. C., Edwards P. C., Runswick M. J., Jakes R., et al. (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(12), 4506–4510.PubMedGoogle Scholar
  220. Woodgett J. R. (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9(8), 2431–2438.PubMedGoogle Scholar
  221. Yamada T., McGeer P. L., and McGeer E. G. (1992) Appearance of paired nucleated, Tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neurosci. Lett. 135(1), 99–102.PubMedGoogle Scholar
  222. Yamazaki M., Nakano I., Imazu O., Kaieda R., and Terashi A. (1994) Astrocytic straight tubules in the brain of a patient with Pick’s disease. Acta Neuropathol. (Berl) 88(6), 587–591.Google Scholar
  223. Yasuda M., Takamatsu J., D’Souza I., Crowther R. A., Kawamata T., et al. (2000) A novel mutation at posititon +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann. Neurol. 47(4), 422–429.PubMedGoogle Scholar
  224. Yoshida H. and Ihara Y. (1993) Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. J. Neurochem. 61(3), 1183–1186.PubMedGoogle Scholar
  225. Zheng-Fischhofer Q., Biernat J., Mandelkow E. M., Illenberger S., Godemann R., and Mandelkow E. (1998) Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur. J. Biochem. 252(3), 542–552.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Makoto Higuchi
    • 1
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
  1. 1.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphia

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