Abstract
Tau accumulating as paired helical filaments (PHF) in Alzheimer's disease brain is considered to be abnormally phosphorylated on distinct sites. To compare the phosphorylation state of tau-positive neuronal inclusions among diverse neurologic diseases, we have probed these lesions with three well-defined PHF/tau monoclonals, C5, M4 and tau 1, that most likely recognize three proline-directed phosphorylation sites in PHF-tau. In Alzheimer's disease brain all three monoclonals intensely immunostained intracellular neurofibrillary tangles, neuropil threads, senile plaque neurites, and “pretangle neurons” in a phosphorylation-dependent manner. They also stained, in the same manner, Pick bodies in Pick's disease, and neurofibrillary tangles and neuropil threads in various tangle-forming neurologic diseases. In most of these diseases (including Pick's disease, progressive supranuclear palsy, subacute sclerosing panencephalitis, and Alzheimer's disease) astrocytes and oligodendrocytes were found to contain tau-positive inclusions which showed the same immunocytochemical characteristics. Thus, the widely occurring tau-positive inclusions share common phosphorylation characteristics irrespective of underlying diseases or cell types.
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Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal K, Iqbal K, Wisniewski HM (1989) Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res 477: 90–99
Biernat J, Mandelkow E-M, Schröter C, Lichtenberg-Kraag B, Steiner B, Berling B, Meyer H, Mercken M, Vandermeeren A, Goedert M, Mandelkow E (1992) The switch of tau protein to an Alzheimer-like state includes the phosphorylations of two serine-proline motifs upstream of the microtubule binding region. EMBO J 11: 1593–1597
Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101: 1371–1378
Drewes G, Lichtenberg-Kraag B, Doring F, Mandelkow E-M, Biernat J, Goris J, Doree M, Mandelkow E (1992) Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J 11: 2131–2138
Eidelberg D, Sotrel A, Joachim C, Selkoe D, Forman A, Pendlebury WW, Perl DP (1987) Adult onset Hallervorden-Spatz disease with neurofibrillary pathology. A discrete clinicopathological entity. Brain 110: 993–1013
Flament S, Delacourte A, Verny M, Hauw J-J, Javoy-Agid F (1991) Abnormal tau proteins in progressive supranuclear palsy. Similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol 81: 591–596
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequence and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3: 519–526
Hasegawa M, Morishima-Kawashima M, Takio K, Suzuki M, Titani K, Ihara Y (1992) Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J Biol Chem 267: 17047–17054
Hasegawa M, Watanabe A, Takio K, Suzuki M, Arai T, Titani K, Ihara Y (1993) Characterization of two distinct monoclonal antibodies to paired helical filaments (PHF): further evidence for fetal-type phosphorylation of the tau in paired helical filaments. J Neurochem 60: 2068–2077
Hellmich MR, Pant HC, Wada E, Battey JF (1992) Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci USA 89: 10867–10871
Ishiguro K, Takamatsu M, Tomizawa K, Omori A, Takahashi M, Arioka M, Uchida T, Imahori K (1992) Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J Biol Chem 267: 10897–10901
Joachim CL, Morris JH, Kosik KS, Selkoe DJ (1987) Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders. Ann Neurol 22: 514–520
Kanai Y, Takemura RE, Oshima T, Mori H, Ihara Y, Yanagisawa M, Masaki T, 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
Kanemaru K, Takio K, Miura R, Titani K, Ihara Y (1992) Fetal-type phosphorylation of the τ in paired helical filaments. J Neurochem 58: 1667–1675
Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer's disease. Nature 197: 192–193
Kosik KS, Orecchio LD, Binder LI, Trojanowski JQ, Lee VM-Y, Lee G (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1: 817–825
Kumpulainen T, Dahl D, Korhonen K, Nystrom SHM (1983) Immunolabeling of carbonic anhydrase isoenzyme C and glial fibrillary acidic protein in paraffin-embedded tissue sections of human brain and retina. J Histochem Cytochem 31: 879–886
Lee VM-Y, Balin BJ, Otvos L, Trojanowski JQ (1991) A68; a major subunit of paired helical filaments and derivatized forms of normal tau. Science 251: 675–678
Love S, Saitoh T, Quijada S, Cole GM, Terry RD (1988) Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropathol Exp Neurol 47: 393–405
Mandelkow E-M, Drewes G, Biernat J, Gustke N, Lint JV, Vandenheede JR, Mandelkow E (1992) Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett 314: 315–321
Migheli A, Butler M, Brown K, Shelanski ML (1988) Light and electron microscope localization of the microtubule-associated tau protein in rat brain. J Neurosci 8: 1846–1851
Nakano I, Iwatsubo T, Otsuka N, Kamei M, Matsumura K, Mannen T (1992) Paired helical filaments in astrocytes: electron microscopy and immunohistochemistry in a case of atypical Alzheimer's disease. Acta Neuropathol 83: 228–232
Nishimura M, Namba Y, Ikeda K, Oda M (1992) Glial fibrillary tangles with straight tubules in the brains of patients with PSP. Neurosci Lett 143: 35–38
Papasozomenos SC (1989) Tau protein immunoreactivity in dementia of the Alzheimer type. II. Electron microscopy and pathogenetic implications. Lab Invest 60: 375–389
Papasozomenos SC, Binder LI (1987) Phosphorylation determines two distinct species of tau in the central nervous system. Cell Motil Cytoskeleton 8: 210–226
Probst A, Langui D, Lautenschlager C, Ulrich J, Brion JP, Anderton BH (1988) Progressive supranuclear palsy; extensive neuropil threads in addition to neurofibrillary tangles. Very similar antigenicity of subcortical neuronal pathology in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol 77: 61–68
Rasool CG, Selkoe DJ (1985) Sharing of specific antigens by degenerating neurons in Pick's disase and Alzheimer's disease. N Engl J Med 312: 700–705
Roberts GW (1988) Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis. Lancet II: 1456–1458
Schmidt ML, Lee VM-Y, Hurtig H, Trojanowski JQ (1988) Properties of antigenic determinants that distinguish neurofibrillary tangles in progressive supranuclear palsy and Alzheimer's disease. Lab Invest 59: 460–466
Shankar SK, Yanagihara R, Garruto RM, Grundke-Iqbal I, Kosik K, Gajdusek C (1989) Immunocytochemical characterization of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Ann Neurol 25: 146–151
Shin R-W, Iwaki T, Kitamoto T, Tateishi J (1991) Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues. Lab Invest 64: 693–702
Tabaton M, Mandybur TL, Perry G, Onorato M, Autilio-Gambetti L, Gambetti P (1989) The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition. Ann Neurol 26: 771–778
Terry RD, Gonatas NK, Weiss M (1964) Ultrastructural studies in Alzheimer's presenile dementia. Am J Pathol 44: 269–297
Watanabe A, Hasegawa M, Suzuki M, Takio K, Morishima-Kawashima M, Titani K, Arai T, Kosik KS, Ihara Y (1993) In vivo phosphorylation sites in fetal and adult rat tau. J Biol Chem 268: 257/2–257/7
Weingarten MD, Lockwood AH, Hwo S-Y, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72: 1858–1862
Wille H, Drewes G, Biernat J, Mandelkow E-M, 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
Wisniewski K, Jervis GA, Moretz RC, Wisniewski HM (1979) Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia. Ann Neurol 5: 288–294
Yamada T, McGeer PL (1990) Oligodendroglial microtubular masses: an abnormality observed in some human neurodegenerative diseases. Neurosci Lett 120: 163–166
Yamada T, McGeer PL, McGeer EG (1992) Appearance of paired nucleated, tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neurosci Lett 135: 99–102
Yamada T, Calne DB, Akiyama H, McGeer EG, McGeer PL (1993) Further observations on tau-positive glia in the brains with progressive supranuclear palsy. Acta Neuropathol 85: 308–315
Yoshida H, Ihara Y (1993) τ in paired helical filaments (PHF) is functionally distinct from fetal tau: assembly incompetence of PHF-tau. J Neurochem 61: 1183–1186
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Supported by Grants-in-Aid for Specially Promoted Reseach (no. 03102008) and for Scientific Research on Priority Areas (no. 05261203 and 05251205) from the Ministry of Education, Science and Culture, and a Grant-in-Aid for Scientific Research from the Ministry of Health and Welfare, Japan
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Iwatsubo, T., Hasegawa, M. & Ihara, Y. Neuronal and glial tau-positive inclusions in diverse neurologic diseases share common phosphorylation characteristics. Acta Neuropathol 88, 129–136 (1994). https://doi.org/10.1007/BF00294505
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DOI: https://doi.org/10.1007/BF00294505