Abstract
Differential distribution and phosphorylation of tau proteins were studied in developing kitten brain by using several antibodies, and was compared to phosphorylation in Alzheimer's disease. Several antibodies demonstrated the presence of phosphorylated tau proteins during kitten brain development and identified pathological structures in human brain tissue. Antibody AD2, recognized tau in kittens and adult cats, but reacted in Alzheimer's tissue only with a pathological tau form. Antibody AT8 was prominent in developing kitten neurons and was found in axons and dendrites. After the first postnatal month this phosphorylation type disappeared from axons. Furthermore, dephosphorylation of kitten tau with alkaline phosphatase abolished immunoreactivity of AT8, but not that of AD2, pointing to a protection of the AD2 epitope in cats. Tau proteins during early cat brain development are phosphorylated at several sites that are also phosphorylated in paired helical filaments during Alzheimer's disease. In either event, phosphorylation of tau may play a crucial role to modulate microtubule dynamics, contributing to increased microtubule instability and promoting growth of processes during neuronal development or changing dynamic properties of the cytoskeleton and contributing to the formation of pathological structures in neurodegenerative diseases.
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References
Arendt, T. (2001) Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience 102, 723–765.
Baudier, J. & Cole, R. D. (1987) The phosphorylation of the microtubule-associated tau proteins. In Alterations in the Neuronal Cytoskeleton in Alzheimer Disease (edited by Perry, G.). pp. 25–32. New York: Plenum Publishing Co.
Biernat, J., Mandelkow, E.-M., Schroeter, C., Lichtenberg-Kraag, B., Steiner, B., Berling, B., Meyer, H., Mercken, M., Vanermeeren, 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 Journal 11, 1593–1597.
Biernat, J., Gustke, N., Drewes, G., Mandelkow, E.-M. & Mandelkow, E. (1993) Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: Distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11, 153–163.
Biernat, J. & Mandelkow, E.-M. (1999) The development of cell processes induced by tau proteins requires phosphorylation of serine 262 and 356 in the repeat domain and is inhibited by phosphorylation in the proline rich domains. Molecular Biology of the Cell 10, 727–740.
Binder, L. I., Frankfurter, A. & Rebhun, L. I. (1985) The distribution of tau polypeptides in the mammalian central nervous system. Journal of Cell Biology 103, 1371–1378.
Braak, H., Braak, E. & Bohl, J. (1993) Staging of Alzheimer-related cortical destruction. Reviews in Clinical Neuroscience 33, 403–408.
Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q. & Lee, V. M.-Y. (1993) Abnormal tau phosphorylation at ser 396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089–1099.
Brandt, R., Leger, J. & Lee, G. (1995) Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. Journal of Cell Biology 131, 1327–1340.
Brion, J. P., Guilleminot, J., Couchie, D., Flament-Durand, J. & Nunez, J. (1988) Both adult and juvenile tau microtubule-associated proteins are axon specific in the developing and adult rat cerebellum. Neuroscience 25, 139–146.
Brion, J.-P., Octave, J. N. & Couck, A. M. (1994) Distribution of the phosphorylated microtubule-associated protein tau in developing cortical neurons. Neuroscience 63, 895–909.
Buee-Scherrer, V., Buee, L., Hof, P. R., Leveugle, B., Gilles, C., Loerzel, A. J., Perl, D. P. & Delacourte, A. (1995) Neurofibrillary degeneration in amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: Immunochemical characterization of tau proteins. American Journal of Pathology 68, 924–932.
Buee-Scherrer, V., Hof, P. R., Buee, L., Leveugle, B., Vermersch, P., Perl, D. P., Olanow, C. W. & Delacourte, A. (1996a) Hyperphosphorylated tau protein doublest in corticobasal degeneration and Pick's disease. Acta Neuropathologica 91, 351–359.
Buee-Scherrer, V., Condamines, O., Mourtongilles, C., Jakes, R., Goedert, M., Pau, B. & Delacourte, A. (1996b) AD2, a phosphorylation-dependent monoclonal antibody directed against tau proteins found in Alzheimer's disease. Molecular Brain Ressearch 39, 79–88.
Burack, M. A. & Halpain, S. (1996) Site-specific regulation of Alzheimer-like tau phosphorylation in living neurons. Neuroscience 72, 167–184.
Condamines, O., Buee-Scherrer, V., Boissier, L., Wattez, A., Delacourte, A., Pau, B. & Mourton-Gilles, C. (1995) New immunoassay for the mapping of neurofibrillary degeneration in Alzheimer's disease using two monoclonal antibodies against human paired helical filament tau proteins. Neuroscience Letters 192, 81–84.
Crowther, R. A. (1993) Tau protein and paired helical filaments of Alzheimer's disease. Current Oppinion in Structural Biology 3, 202–206.
Delacourte, A. (1999) Biochemical and molecular characterization of neurofibrillary degeneration in frontotemporal dementias. Dementia and Geriatric Cognitive Disorders, Suppl. 1, 75–79.
Delacourte, A., David, J. P., Sergeant, N., Buee, L., Wattez, A., Vermersch, P., Ghozali, F., Fallet-Bianco, C., Pasquier, F., Lebert, F., Petit, F. & Dimenza, C. (1999) The biochemical pathways of neurofibrillary degenertaion in aging and Alzheimer's disease. Neurology 52, 1158–1165.
Drewes, G., Ebneth, A. & Mandelkow, E. M. (1998) MAPs, MARKS and microtubule dynamics. Trends in Biochemical Sciences 23, 307–311.
Drubin, D. G., Caput, D. & Kirschner, M. W. (1984) Studies on the expression of the microtubule-associated protein, tau, during mouse brain development with newly isolated complementary cDNA probes. Journal of Cell Biology 98, 1090–1097.
Drubin, D. G. & Kirschner, M. W. (1986) Tau protein function in living cells. Journal of Cell Biology 103, 2739–2746.
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. Developmental Brain Research 34, 9–31.
Frey, P., Sunderji, S. & Waridel, C. (1997) Search for inhibitors of tau hyperphosphorylation. In Alzheimer's Disease: Biology, Diagnosis and Therapeutics (edited by Iqbal, K., Winblad, B., Nishimura, T., Takeda, M. & Wisniewski, H. M.) pp. 449–455. New York: John Wiley.
Gartner, U., Janke, C., Holzer, M., Vanmeichelein, E. & Arendt, T. (1998) Postmortem changes in the phosphorylation state of tau protein in the rat brain. Neurobiology of Aging 19, 535–543.
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 Journal 9, 4225–4230.
Goedert, M., Spillantini, M. G., Cairns, N. J. & Crowther, R. A. (1992) Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168.
Goedert, M., Jakes, R., Crowther, R. A., Six, J., Lubke, U., Vandermeeren, M., Cras, P., Trojanowski, J. Q. & Lee, V. M.-Y. (1993) The abnormal phosphorylation of tau protein at Ser202 in Alzheimer disease recapitulates phosphorylation during development. Proceedings of the National Academy of Sciences of the USA 90, 5066–5070.
Goedert, M., Jakes, R. & Vanmechelen, E. (1995) Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205. Neuroscience Letters 189, 167–170.
Hanger, D. P., Betts, J. C., Loviny, T. L. F., Blackstock, W. P. & Anderton, B. H. (1998) New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer's disease brain using nanoelectrospray mass spectrometry. Journal of Neurochemistry b/d71, 2465–2476.
Harrison, L., Cheetham, M. E. & Calvert, R. A. (1993) Investigation of the changes in neuronal distribution and phosphorylation state of MAP1X during development. Developmental Neurosciences 15, 68–76.
Hasegawa, M., Jakes, R., Crowther, R. A., Lee, V. M.-Y., Ihara, Y. & Goedert, M. (1996) Characterization of MAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein. FEBS Letters 384, 25–30.
Himmler, A. (1989) Structure of the bovine tau gene: Alternatively spliced transcripts generate a protein family. Molecular Cell Biology 9, 1389–1396.
Iqbal, K., Zaidi, T., Bancher, C. & Grundkeiqbal, I. (1994) Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Letters 349, 104–108.
Jicha, G. A., Berenfeld, B. & Davies, P. (1999) Sequence requirements for formation of conformational variants of tau similar to those found in Alzheimer's disease. Journal of Neuroscience Research 55, 713–723.
Kanai, Y., Chen, J. & Hirokawa, N. (1992) Microtubule bundling by tau proteins in vivo: Analysis of functional domains. EMBO Journal 11, 3953–3961.
Lee, G. (1990) Tau protein: An update on structure and function. Cell Motility and the Cytoskeleton 15, 199–203.
Lenette, D. A. (1978) An improved mounting medium for immunofluorescence microscopy. American Journal of Clinical Pathology 69, 647–648.
Liberini, P., Valerio, A., Moretto, G., Rizzonelli, P., Memo, M., Rizzutto, N. & Spano, P. F. (1995) Tau protein immunolocalization in fetal and adult human spinal cord. Neurocience Research 22, 197–202.
Lindwall, G. & Cole, R. D. (1984) Phosphorylation affects the ability of tau protein to promote microtubule assembly. Journal of Biological Chemistry 259, 5301–5305.
Lu, Q. & Wood, J. G. (1993) Functional studies of Alzheimer's disease tau protein. Journal of Neurosciences 13, 508–515.
Maillot, C., Sergeant, N., Bussiere, T., Caillet-Boudin, M. L., Delacourte, A. & Buee, L. (1998) Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes. FEBS Letters 433, 201–204.
Mandelkow, E. M. & Mandelkow, E. (1998) Tau in Alzheimer's disease. Trends in Cell Biology 8, 425–427.
matsuoe.s. shinr. w. & billingsleym.l. vandevoordea. o'conrm trojawskij.q. & leev. 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.
Mercken, M., Vandermeeren, M., Lubcke, U., Six, J., Boons, J., van de Voorde, A., Martin, J.-J. & Gheuens, J. (1992) Monoclonal antibodies with selective specificity of Alzheimer tau are directed against phosphatase-sensitive epitopes. Acata Neuropathologica 84, 265–272.
Migheli, A., Butler, M., Brown, K. & Shelanski, M. L. (1988) Light and electron microscope localization of the microtubule-associated tau protein in rat brain. Journal of Neurosciences 8, 1846–1851.
Morishima, M. & Ihara, Y. (1994) Posttranslational modifications of tau in paired helical filaments. Dementia 5, 282–288.
Nothias, F., Boyne, L., Murray, M., Tessler, A. & Fischer, I. (1995) The expression and distribution of Tau proteins and messenger RNA in rat dorsal root ganglion neurons during development and regeneration. Neuroscience 66, 707–719.
Papasozomenos, S. C. & Binder, L. I. (1987) Phosphorylation determines two distinct species of tau in the central nervous system. Cell Motility and the Cytoskeleton 8, 210–226.
Pasquier, F. & Delacourte, A. (1998) Non-Alzheimer degenerative dementias. Current Oppinion in Neurology 11, 417–427.
Pope, W., Enam, S. A., Bawa, N., Miller, B. E., Ghanbari, H. A. & Klein, W. L. (1993) Phosphorylated tau epitope of Alzheimer's disease is coupled to axon development in the avian central nervous system. Experimental Neurology 120, 106–113.
Probst, A., Langui, D. & Ulrich, J. (1991) Alzheimer's disease: A description of the structural lesions. Brain Pathology 1, 1229–1239.
Riederer, B. M., Guadno-Ferraz, A. & Innocenti, G. M. (1990) Difference in distribution of microtubule-associated protein 5a and 5b during the development of cerebral cortex and corpus callosum in cats: Dependence on phosphorylation. Developmental Brain Research 56, 235–243.
Riederer, B. M. & Innocenti, G. M. (1991) Differential distribution of tau proteins in developing cat cerebral cortex and corpus callosum. European Journal of Neuroscience 3, 1134–1145.
Riederer, B. M. & Binder, L. I. (1994) Differential distribution of tau proteins in developing cat cerebellum. Brain Research Bulletin 33, 155–161.
Riederer, B. M., Pellier, V., Antonsson, B., Dipaolo, G., Stimpson, S. A., Lutjens, R., Catsicas, S. & Grenningloh, G. (1997) Regulation of microtubule dynamics by the neuronal growthassociated protein SCG10. Proceedings of the National Academy of Sciences of the USA 94, 741–745.
Roesner, H., Rebhan, M., Vacun, G. & Vanmechelen, E. (1995) Developmental expression of tau proteins in the chicken and rat brain: Rapid down-regulation of a paired helical filament epitope in the rat cerebral cortex coincides with the transition from immature to adult tau isoforms. International Journal of Developmental Neuroscience 13, 607–617.
Sergeant, N., Bussiere, T., Vermersch, P., Lejeune, J. P. & Delacourte, A. (1995) Isoelectric point differentiates PHF-tau from biopsy-derived human brain tau proteins. NeuroReport 6, 2221–2224.
Shea, T. B. & Cressman, C. M. (1999) The order of exposure of tau to signal transduction kinases alters the generation of “AD-like” phosphoepitopes. Cell and Molecular Neurobiology 19, 223–233.
Spillantini, M. G. & Goedert, M. (1998) Tau protein pathology in neurodegenerative diseases. Trends in Neurosciences 21, 428–433.
Szendrei, G. I., Lee, V. M.-Y. & Otvos, Jr L. (1993) Recognition of the minimal epitope of monoclonal antibody TAU-1 depends upon the presence of a phosphate group but not its location. Journal of Neuroscience Research 34, 243–249.
Trinczek, B., Biernat, J., Baumann, K., Mandelkow, E.-.M. & Mandelkow, E. (1995) Domains of tau proteins, differential phosphorylation, and dynamic instability microtubules. Molecular Biology of the Cell 6, 1887–1902.
Trojanowski, J. Q. & Lee, V. M.-Y. (1997) Phosphorylation of paired helical filament tau in Alzheimer's disease neurofibrillary lesions: Focusing on phosphatases. FASEB Journal 9, 1570–1576.
Tseng, H. C., Lu, Q., Henerson, E. & Graves, D. J. (1999) Phosphorylated tau can promote tubulin assembly. Proceedings of the National Academy of Sciences of the USA 96, 9503–9508.
Watanabe, A., Hasegawa, M., Suzuki, M., Takio, K., Moroshima-Kawahima, M., Arai, K., Kosik, K. S. & Ihara, Y. (1993) In vivo phosphorylation sites in fetal and adult rat tau. Journal of Biological Chemistry 268, 25712–25717.
Yoshida, H. & Ihara, Y. (1993) Tau in paired helical filaments is functionally distinct from fetal tau: Assembly incompetence of paired helical filament-tau. Journal of Neurochemistry 61, 1183–1186.
Zhang, J. & Johnson, G. V. W. (2000) Tau protein is hyperphosphorylated in a site-specific manner in apoptotic neuronal PC12 cells. Journal of Neurochemistry 75, 2346–2357.
Zhong, J., Iqbal, K. & Grundke-Iqbal, I. (1999) Hyperphosphorylated tau in SY5Y cells: Similarities and dissimilaritis to abnormally hyperphosphorylated tau from Alzheimer's disease brain. FEBS Letters 453, 224–228.
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Riederer, B.M., Mourton-Gilles, C., Frey, P. et al. Differential phosphorylation of tau proteins during kitten brain development and Alzheimer's disease. J Neurocytol 30, 145–158 (2001). https://doi.org/10.1023/A:1011991207942
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DOI: https://doi.org/10.1023/A:1011991207942