Skip to main content
SpringerLink
Log in

A Phosphorylated Tau Species Is Transiently Present in Developing Cortical Neurons and Is Not Associated with Stable Microtubules

  • Conference paper
Book cover Alzheimer’s Disease: Lessons from Cell Biology

Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

  • 91 Accesses

Summary

During brain development, the microtubule-associated protein tau presents a transient state of high phosphorylation, similar to the phosphorylation status of paired helical filaments-tau in Alzheimer’s disease. We have investigated the developmental distribution of this phosphorylated foetal-type tau in the developing rat cortex and in cultures of embryonic cortical neurons using antibodies that react with tau in a phosphorylation-dependent manner. The phosphorylated foetal-type tau was present in the developing cortex at 20 days but not at 18 days of embryonic life and was not detected before 4–5 days in neuronal culture. The cyclin-dependent kinase p34cdc2 was expressed only in germinal layers in the embryonic brain and was not co-localized with phosphorylated tau. After 10 days of postnatal life, this phosphorylated tau progressively disappeared from cortical neurons, disappearing first from the deepest cortical layers where neurons are onto-genetically the oldest. This phosphorylated tau was found in axons and dendrites of cortical neurons at all developmental stages, whereas unphosphorylated tau tended to disappear from dendrites during development. The timing of appearance of phosphorylated tau in the cortex, by comparison with the expression of other developmental markers, indicates that phosphorylated tau is present at a high level only during the period of intense neuritic outgrowth and that it disappears during the period of neurite stabilization and synaptogenesis, concomitant with the expression of adult tau isoforms. In control cultures and in cultures treated with colchicine, this phosphorylated tau was not associated with cold-stable and colchicine-resistant microtubules.

These in vivo results suggest that the high expression of this phosphorylated tau species is correlated with the presence of a dynamic microtubule network during a period of high plasticity in the developing brain.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Bass PW, Pienkowski TP, Kosik KS (1991) Processes induced by tau expression in Sf9 cells have an axon-like microtubule organization. J Cell Biol 115: 1333–1344

    Article  Google Scholar 

  • Benowitz LI, Apostolides PJ, Perrone-Bizzozero N, Finklestein SP, Zwiers H (1988) Anatomical distribution of the growth-associated protein GAP-43/B50 in the adult rat brain. J Neurosci 8: 339–352

    PubMed  CAS  Google Scholar 

  • 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 phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO J 11: 1593–1597

    PubMed  CAS  Google Scholar 

  • Binder LI, Frankfurter A, Rebhun I (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101: 1371–1378

    Article  PubMed  CAS  Google Scholar 

  • Bloom GS, Luca FC, Valee RB (1985) Microtubule-associated protein 1B: identification of a major component of the neuronal cytoskeleton. Proc Natl Acad Sci USA 82: 5404–5408

    Article  PubMed  CAS  Google Scholar 

  • Brady ST, Tytell M, Lasek RJ (1984) Axonal tubulin and axonal microtubules: biochemical evidence for stability. J Cell Biol 99: 1716–1724

    Article  PubMed  CAS  Google Scholar 

  • Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JO, Lee VM-Y (1993). Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 10: 1089–1099

    Article  PubMed  CAS  Google Scholar 

  • Brion JP, Passareiro H, Nunez J, 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 (Brux) 95: 229–235

    Google Scholar 

  • Brion JP, Guilleminot J, Couchie D, Nunez J (1988) Both adult and juvenile tau microtubuleassociated proteins are axon specific in the developing and adult rat cerebellum. Neuroscience 25: 139–146

    Article  PubMed  CAS  Google Scholar 

  • Brion JP, Hanger DP, Bruce MT, Couck AM, Flament-Durand J, Anderton BH (1991a) 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

    Google Scholar 

  • Brion JP, Hanger DP, Couck AM, Anderton BH (1991b) A68 proteins in Alzheimer’s disease are composed of several tau isoforms in a phosphorylated state which affects their electrophoretic mobilities. Biochem J 279: 831–836

    PubMed  CAS  Google Scholar 

  • Brion JP, Smith C, Couck AM, Gallo JM, Anderton BH (1993) Developmental changes in tau phosphorylation: fetal-type tau is transiently phosphorylated in a manner similar to paired helical filament-tau characteristic of Alzheimer’s disease. J Neurochem 61: 2071–2080

    Article  PubMed  CAS  Google Scholar 

  • Caceres A, Kosik KS (1990) Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 343: 461–463

    Article  PubMed  CAS  Google Scholar 

  • Calvert R, Anderton BH (1985) A microtubule-associated protein (MAP1) which is expressed at elevated levels during development of the rat cerebellum. EMBO J 4: 1171–1176

    PubMed  CAS  Google Scholar 

  • Cleveland DW, Hwo SY, Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116: 207–225

    Article  PubMed  CAS  Google Scholar 

  • Couchie D, Nunez J (1985) Immunological characterization of microtubule-associated proteins specific for the immature brain. FEBS Lett 188: 331–335

    Article  PubMed  CAS  Google Scholar 

  • Couchie D, Faivre-Bauman A, Puymirat J, Guilleminot J, Tixier-Vidal A, Nunez J (1986) Expression of microtubule-associated proteins during the early stages of neurite extension by brain neurons cultured in a defined medium. J Neurochem 47: 1255–1261

    Article  PubMed  CAS  Google Scholar 

  • Couchie D, Legay F, Guilleminot J, Lebargy F, Brion J-P, Nunez J (1990) Expression of Tau protein and Tau mRNA in the cerebellum during axonal outgrowth. Exp Brain Res 82: 589–596

    Article  PubMed  CAS  Google Scholar 

  • Crandall JE, Jacobson M, Kosik KS (1986) Ontogenesis of microtubule-associated protein 2 (MAP2) in embryonic mouse cortex. Dev Brain Res 28: 127–133

    Article  CAS  Google Scholar 

  • Delacourte A, Defossez A (1986) Alzheimer’s disease: tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J Neurol Sci 76: 173–186

    Article  PubMed  CAS  Google Scholar 

  • Dotti CG, Banker GA, Binder LI (1987) The expression and distribution of the microtubuleassociated proteins tau and microtubule-associated protein 2 in hippocampal neurons in the rat in situ and in cell culture. Neuroscience 23: 121–130

    Article  PubMed  CAS  Google Scholar 

  • Drewes G, Lichtenberg-Kraag B, Döring F, Mandelkow E-M, Biernat J, Goris J, Dorée M, Mandelkow E (1992) Mitogen activated protein ( MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J 11: 2131–2138

    Google Scholar 

  • Drubin DG, Kirschner MW (1986) Tau protein function in living cells. J Cell Biol 103: 2739–2746

    Article  PubMed  CAS  Google Scholar 

  • Ferreira A, Busciglio J, Caceres A (1987) An immunocytochemical analysis of the ontogeny of the microtubule-associated proteins MAP-2 and tau in the nervous system of the rat. Dev Brain Res 34: 9–31

    Article  CAS  Google Scholar 

  • Ferreira A, Busciglio J, Caceres A (1989) Microtubule formation and neurite growth in cerebellar macroneurons which develop in vitro: evidence for the involvement of the microtubule-associated proteins, MAP-la, HMW-MAP2 and Tau. Dev Brain Res 49: 215–228

    Article  CAS  Google Scholar 

  • Francon J, Lennon AM, Fellows A, Mareck A, Pierre M, Nunez J (1982) Heterogeneity of microtübule-associated proteins and brain development. Eur J Biochem 129: 465–471

    Article  PubMed  CAS  Google Scholar 

  • Gallo J-M, Hanger DP, Twist EC, Kosik KS, Anderton BH (1992) Expression and phosphorylation of a three-repeat isoform of tau in transfected non-neuronal cells. Biochem J 286: 399–404

    PubMed  CAS  Google Scholar 

  • Goedert M, 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: 4225–4230

    Google Scholar 

  • Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the eDNA 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: 4051–4055

    Article  PubMed  CAS  Google Scholar 

  • Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3: 519–526

    Article  PubMed  CAS  Google Scholar 

  • Goedert M, Jakes R, Crowther RA, Six J, Lübke U, Vandermeeren M, Cras P, Trojanowski JQ, Lee VM-Y (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci USA 90: 5066–5070

    Article  PubMed  CAS  Google Scholar 

  • Goslin K, Schreyer DJ, Skene JHP, Banker G (1988) Development of neuronal polarity: GAP-43 distinguishes axonal from dendritic growth cones. Nature 336: 672–674

    Article  PubMed  CAS  Google Scholar 

  • Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubuleassociated protein tau: a component of Alzheimer paired helical filaments. J Biol Chem 261: 6084–6089

    PubMed  CAS  Google Scholar 

  • Jacobson RD, Virag I, Skene JHP (1986) A protein associated with axon growth, GAP-43, is widely distributed and developmentally regulated in rat CNS. J Neurosci 6: 1843–1855

    PubMed  CAS  Google Scholar 

  • Kanai Y, Takemura R, Oshima T, Mori H, Ihara Y, Yanagisawa M, Masaki T, Kirokawa 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

    Article  PubMed  CAS  Google Scholar 

  • Kanemaru K, Takio K, Miura R, Titani K, Ihara Y (1992) Fetal-type phosphorylation of the r in paired helical filaments. J Neurochem 58: 1667–1675

    Article  PubMed  CAS  Google Scholar 

  • Kenessey A, Yen S-HC (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

    Article  PubMed  CAS  Google Scholar 

  • Knaus P, Betz H, Rehm H (1986) Expression of synaptophysin during postnatal development of the mouse brain. J Neurochem 47: 1302–1304

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi S, Ishiguro K, Omori A, Takamatsu M, Arioka M, Imahori K, 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 microtubule. FEBS Lett 335: 171–175

    Article  PubMed  CAS  Google Scholar 

  • Kosik KS, Finch EA (1987) MAP2 and tau segregate into dendritic and axonal domains after the elaboration of morphologically distinct neurites: an immunocytochemical study of cultures rat cerebrum. J Neurosci 7: 3142–3153

    PubMed  CAS  Google Scholar 

  • Kosik KS, Joachim CL, Selkoe DJ (1986) The microtubule-associated protein, tau, is a major antigenic component of paired helical filaments in Alzheimer’s disease. Proc Natl Acad Sci USA 83: 4044–4048

    Article  PubMed  CAS  Google Scholar 

  • Kosik KS, Orecchio LD, Bakalis S, Neve RL (1989) Developmentally regulated expression of specific tau sequences. Neuron 2: 1389–1397

    Article  PubMed  CAS  Google Scholar 

  • Ledesma MD, Correas I, Avila J, Díaz-Nido J (1992) Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer’s disease. FEBS Lett 308: 218–224

    Article  PubMed  CAS  Google Scholar 

  • Lee VMY, Balin BJ, Otvos L, Trojanowski JQ (1991) A68 proteins are major subunits of Alzheimer disease paired helical filaments and derivatized forms of normal tau. Science 251: 675–678

    Article  PubMed  CAS  Google Scholar 

  • Lindwall G, Cole RD (1984) Phosphorylation affects the ability of tau protein to promote microtubule’assembly. J Biol Chem 259: 5301–5306

    PubMed  CAS  Google Scholar 

  • Litman P, Barg J, Rindzoonski L, Ginzburg I (1993) Subcellular localization of tau mRNA in differentiating neuronal cell culture: Implications for neuronal polarity. Neuron 10: 627–638

    Google Scholar 

  • Liu W-K, Moore WT, Williams RT, Hall FL, Yen S-H (1993) Application of synthetic phospho-and unphospho-peptides to identify phosphorylation sites in a subregion of the tau molecule, which is modified in Alzheimer’s disease. J Neurosci Res 34: 371–376

    Article  PubMed  CAS  Google Scholar 

  • Lo MMS, Fieles AW, Norris TE, Dargis PG, Caputo CB, Scott CW, Lee VM-Y, Goedert M (1993) Human tau isoforms confer distinct morphological and functional properties to stably transfected fibroblasts. Mol Brain Res 20: 209–220

    Article  PubMed  CAS  Google Scholar 

  • Mangin G, Couchie D, Charrière-Bertrand C, Nunez J (1989) Timing of expression of r and its encoding mRNAs in the developing cerebral neocortex and cerebellum of the mouse. J Neurochem 53: 45–50

    Article  PubMed  CAS  Google Scholar 

  • Mattson MP (1992) Effects of microtubule stabilization and destabilization on tau immunoreactivity in cultured hippocampal neurons. Brain Res 582: 107–118

    Article  PubMed  CAS  Google Scholar 

  • Matus A (1991) Microtubule-associated proteins and neuronal morphogenesis. J Cell Sci 100 Suppl. 15: 61–67

    CAS  Google Scholar 

  • Mercken M, Vandermeeren M, Lübke U, Six J, Boons J, Van De Voorde A, Martin JJ, Gheuens J (1992) Monoclonal antibodies with selective specificity for Alzheimer tau are directed against phosphatase-sensitive epitopes. Acta Neuropathol (Berl) 84: 265–272

    Article  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • Nukina N, Ihara Y (1986) One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem (Tokyo) 99: 1541–1544

    CAS  Google Scholar 

  • Oestreicher AB, Gispen WH (1986) Comparison of the immunocytochemical distribution of the phosphoprotein B-50 in the cerebellum and hippocampus of immature and adult rat brain. Brain Res 375: 267–279

    Article  PubMed  CAS  Google Scholar 

  • Papasozomenos SC, Binder LI (1987) Phosphorylation determines two distinct species of tau in the central nervous system. Cell Motil Cytoskel 8: 210–226

    Article  CAS  Google Scholar 

  • Riederer B, Matus A (1985) Differential expression of distinct microtubule-associated proteins during brain development. Proc Natl Acad Sci USA 82: 6006–6009

    Article  PubMed  CAS  Google Scholar 

  • Riederer BM, Innocenti GM (1991) Differential distribution of tau proteins in developing cat cerebral cortex and corpus callosum. Eur J Neurosci 3: 1134–1145

    Article  PubMed  Google Scholar 

  • Riederer B, Cohen R, Matus A (1986) MAPS: a novel brain microtubule-associated protein under strong developmental regulation. J Neurocytol 15: 763–775

    Article  PubMed  CAS  Google Scholar 

  • Schoenfeld TA, McKerracher L, Obar R, Vallee RB (1989) MAP1A and MAP1B are structurally related microtubule associated proteins with distinct developmental patterns in the CNS. J Neurosci 9: 1712–1730

    PubMed  CAS  Google Scholar 

  • Scott CW, Klika AB, Lo MMS, Norris TE, Caputo CB (1992) Tau protein induces bundling of microtubules in vitro: Comparison of different tau isoforms and a tau protein fragment. J Neurosci Res 33: 19–29

    Google Scholar 

  • Scott CW, Vulliet PR, Caputo CB (1993) Phosphorylation of tau by proline-directed protein kinase (p34cdc2/p58) decreases tau-induced microtubule assembly and antibody SMI33 reactivity. Brain Res 611: 237–242

    Article  PubMed  CAS  Google Scholar 

  • Sygowski LA, Fieles AW, Lo MMS, Scott CW, Caputo CB (1993) Phosphorylation of tau protein in tau-transfected 3T3 cells. Mol Brain Res 20: 221–228

    Article  PubMed  CAS  Google Scholar 

  • Takemura R, Kanai Y, Hirokawa N (1991) In situ localization of tau mRNA in developing rat brain. Neuroscience 44: 393–407

    Article  PubMed  CAS  Google Scholar 

  • Tucker RP (1990) The roles of microtubule-associated proteins in brain morphogenesis: A review. Brain Res Rev 15: 101–120

    Article  PubMed  CAS  Google Scholar 

  • Tucker RP, Garner CC, Matus A (1989) In situ localization of microtubule-associated protein mRNA in the developing and adult rat brain. Neuron 2: 1245–1256

    Article  PubMed  CAS  Google Scholar 

  • Vanisberg MA, Maloteaux JM, Octave JN, Laduron PM (1991) Rapid agonist-induced decrease of neurotensin receptors from the cell surface in rat cultured neurons. Biochem Pharmacol 42: 2265–2274

    Article  PubMed  CAS  Google Scholar 

  • 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: 25712–25717

    PubMed  CAS  Google Scholar 

  • Wischik CM, Novak M, Thogersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, 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

    Article  PubMed  CAS  Google Scholar 

  • Wood JG, Mirra SS, Pollock NJ, Binder LI (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau. Proc Natl Acad Sci USA 83: 4040–4043

    Article  PubMed  CAS  Google Scholar 

  • Yamada KM, Spooner BS, Wessels MK (1970) Axon growth: role of microfilaments and microtubules. Proc Natl Acad Sci USA 66: 1206–1212

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Pathology and Electron Microscopy, Université Libre de Bruxelles, 808 route Lennik, Bldg C-10, 1070, Brussels, Belgium

    J. P. Brion

Authors
  1. J. P. Brion
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. M. Couck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. L. Conreur
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. N. Octave
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Harvard Medical School, Brigham and Women’s Hospital, 221 Longwood Avenue, 02115, Boston, MA, USA

    K. S. Kosik M.D. (Associate Professor of Neurology and Neuroscience) & D. J. Selkoe M.D. (Professor of Neurology and Neuroscience) (Associate Professor of Neurology and Neuroscience) &  (Professor of Neurology and Neuroscience)

  2. Fondation IPSEN, 24, rue Erlanger, 75781, Paris, France

    Y. Christen Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1995 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Brion, J.P., Couck, A.M., Conreur, J.L., Octave, J.N. (1995). A Phosphorylated Tau Species Is Transiently Present in Developing Cortical Neurons and Is Not Associated with Stable Microtubules. In: Kosik, K.S., Selkoe, D.J., Christen, Y. (eds) Alzheimer’s Disease: Lessons from Cell Biology. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79423-0_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-79423-0_13

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-79425-4

  • Online ISBN: 978-3-642-79423-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation