Potential Role of Hyperactivation of Signal Transduction Pathways in Alzheimer’s Disease: Protein Kinase C Regulates PHF-like Phosphorylation of Tau within Neuronal Cells

  • Thomas B. Shea
  • John J. Boyce
  • Corrine M. Cressman
Chapter
Part of the GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia book series (GWUN)

Abstract

Paired helical filaments (PHF) that accumulate in affected neurons in Alzheimer’s disease are comprised of hyperphosphorylated tau that exhibits electrophoretic and antigenic properties distinct from that of normal adult CNS tau (for reviews, see refs. 1–3). Accordingly, one approach towards understanding the onset and progression of Alzheimer’s disease is to determine the kinase(s) responsible for phosphorylating tau.

Keywords

Calpain Activation Calpain Inhibitor Paired Helical Filament Calcium Ionophore A23187 Paired Helical Filament 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Goedert, M., Jakes, R., Crowther, R. A., Six, J., Lubke, U., Vandermeeren, M., Cras, P., Trojanowski, J. Q., and Lee, V. M.-Y. (1993) The abnormal phosphorylation of tau proteins at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc. Natl. Acad. Sci. USA 90:5066–5070.PubMedCrossRefGoogle Scholar
  2. 2.
    Trojanowski, J. Q., Schmidt, M. L., Shin, R.-W., Bramblett, G. T., Rao, D., and Lee, V. M.-Y. (1993) Altered tau and neurofilament proteins in neurodegenative diseases: diagnostic implications for Alzheimer’s disease and Lewy body dementias. Brain Pathol. 3:45–54.PubMedCrossRefGoogle Scholar
  3. 3.
    Trojanowski, J. Q., Schmidt, M. L., Shin, R.-W., Bramblett, G. T., Goedert, M., and Lee, V. M.-Y. (1993) PHF tau (A68): from pathological marker to potential mediator of neuronal dysfunction and degeneration in Alzheimer’s disease. Clin. Neurosci. 1:184–191.Google Scholar
  4. 4.
    Baudier, J. and Cole, D. R. (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. 262:17577–17583.PubMedGoogle Scholar
  5. 5.
    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. 336:417–424.PubMedCrossRefGoogle Scholar
  6. 6.
    Drewes, G., Lichtenberg-Kragg, B., Doring, F., Mandelkow, E.-M., Bienart, J., Doree, M., and Mandelkow, E. (1992) Mitogen activated protein (MAP) kinase transform tau protein into an Alzheimer-like state. EMBO J. 11:2131–2138.PubMedGoogle Scholar
  7. 7.
    Goedert, M., Cohen, E. S., Jakes, R., and Cohen, P. (1992) p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. FEBS Lett. 312:95–99.PubMedCrossRefGoogle Scholar
  8. 8.
    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 localization of the kinase. Neurosci. Lett. 147:58–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Kobayahi S, Ishiguro K, Omori A, Takamatsu M, Arioka M, Imahora K, Uchida T (1993) A cdc-related kinase PSSALRE/cdk5 is homologous with the 30kDa subunit of tau protein kinase II, a proline-directed kinase associated with microtubules. FEBS Lett 335: 171–175.CrossRefGoogle Scholar
  10. 10.
    Ledesma, M. D., Correas, L., Avila, J., and Diaz-Nido, J. (1992) Implication of brain cdc2 and MAP kinases in the phosphorylation of tau protein in Alzheimer’s disease, FEBS Lett. 308: 218–224.PubMedCrossRefGoogle Scholar
  11. 11.
    Mandelkow, E.-M., Drewes, G., Biernat, J., Gustke, N., Van Lint, J., Vandenheede, J. R., and Mandelkow, E. (1992) Glycogen synthase kinase 3 and the Alzheimer’s disease-like state of microtubule-associated protein tau. FEBS Lett. 314:315–321.PubMedCrossRefGoogle Scholar
  12. 12.
    Mulot, S. F. C., Hughes, K., Woodgett, J. R., Anderton, B. H., and Hanger, D. P. (1994) PHF-tau a from Alzheimer’s brain comprises four species on SDS-PAGE which can be mimicked by in vitro phosphorylation of human brain tau by glycogen synthase kinase-3b. FEBS Lett. 349: 359–364.PubMedCrossRefGoogle Scholar
  13. 13.
    Paudel, H. K., Lew, J., Zenobia, A., and Wang, J. H. (1993) Brain proline-directed kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer’s paired helical filaments. J. Biol. Chem. 268: 23512–23518.PubMedGoogle Scholar
  14. 14.
    Vulliet, R., Halloran, S. M., Braun, R. K., Smith, A. J., and Lee, G. (1992) Proline-directed phosphorylation of human tau protein. J. Biol. Chem. 267: 22570–22574.PubMedGoogle Scholar
  15. 15.
    Heikkila JE, Akerlind G and Akerman KEO (1991) Protein kinase C activation and down-regulation in relation to phorbol ester-induced differentiation of SH-SY-5Y human neuroblastoma. J Cell Physiol 140: 593–600.CrossRefGoogle Scholar
  16. 16.
    Leli U, Cataldo AM, Shea TB, Nixon RA and Hauser G (1992a) Distinct mechanisms of differentiation of SH-SY-5Y neuroblastoma cells by protein kinase C activators and inhibitors. J Neurochem 58: 1191–1198.PubMedCrossRefGoogle Scholar
  17. 17.
    Leli U, Parker PJ and Shea TB (1992b) Intracellular delivery of protein kinase C-a or-e isoform-specific antibodies promotes acquisition of a morphologically differentiated phenotype in neuroblastoma cells. FEBS Lett 297: 91–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Minana M-D, Felipo V and Grisolia S (1989) Inhibition of protein kinase C induces differentiation of neuroblastoma cells. FEBS Lett 255: 184–186.PubMedCrossRefGoogle Scholar
  19. 19.
    Ono K, Katayama N, Yamagata Y, Tokunaga A and Tsuda M (1991) Morphology of neurites from N18TG2 cells induced by H-7 and by cAMP. Brain Res Bull 26: 605–612.PubMedCrossRefGoogle Scholar
  20. 20.
    Ono K, Tokunaga A and Tsuda M (1993) Neurite outgrowth from N18TG2 neuroblastoma induced by H-7, a protein kinase inhibitor, in the presence of colchicine. Brain Res Bull 31: 209–215.PubMedCrossRefGoogle Scholar
  21. 21.
    Shea TB and Beermann ML (1991a) Stauroporine-induced morphological differentiation of human neuroblastoma cells. Cell Biol Internat Rep 15: 161–168.CrossRefGoogle Scholar
  22. 22.
    Shea TB, Beermann ML, Leli U and Nixon RA (1992a) Opposing influences of protein kinase activities on neurite outgrowth in human neuroblastoma cells: Initiation by kinase A and restriction by kinase C. J Neurosci Res 33: 398–407.PubMedCrossRefGoogle Scholar
  23. 23.
    Tsuda M, Ono K, Katayama N, Yamagata Y, Kikuchi K and Tsuchiya T (1989) Neurite outgrowth from mouse neuroblastoma and cerebellar cells induced by the protein kinase inhibitor H-7. Neurosci Lett 105: 241–245.PubMedCrossRefGoogle Scholar
  24. 24.
    Murray, A. W., Fournier, A., and Hardy, S. J. (1987) Proteolytic activation of protein kinase C: a physiological reaction? Trends Neurol. Sci. 12:53–54.Google Scholar
  25. 25.
    Hashimoto K, Mikawa K, Kuroda T, Ase K and Kishimoto A (1990) Calpains and regulation of protein kinase C. In: Intracellular calcium-dependent proteolysis (Mellgren RL, Murachi T, eds.) CRC Press Boca Raton, FA pp 181–190.Google Scholar
  26. 26.
    Inoue M, Kishimoto A, Takai Y and Nishizuka Y (1977) Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. II. Proenzyme and its activation by calcium-dependent protease from rat brain. J Biol Chem 252: 7610–7616.PubMedGoogle Scholar
  27. 27.
    Kishimoto A, Kajikawa N, Shiota M and Nishizuka Y (1983) Proteolytic activation of calcium-activated, phospholipid-dependent protein kinase by calcium-dependent neutral protease. J Biol Chem. 258: 1156–1160.PubMedGoogle Scholar
  28. 28.
    Kishimoto A, Mikawa K, Hashimoto K, Yasuda I, Tanaka S-I, Tominaga M, Kurode T and Nishizuka Y (1989) Limited proteolysis of protein kinase C subspecies by calcium-dependent neurtral protease (Calpain) J Biol Chem 264: 4088–4092.PubMedGoogle Scholar
  29. 29.
    Pontremoli, S., Michetti, M., Melloni, E., Sparatore, B., Salamino, F. and Horecker B. L. (1990) Identification of the proteolytically activated form of protein kinase C in stimulated human neurtrophils. Proc. Natl. Acad. Sci. USA 87: 3705–3707.PubMedCrossRefGoogle Scholar
  30. 30.
    Young, S., Parker, P. J., Ulrich, A. and Stable, S. (1987) Down-regulation of protein kinase C is due to an increased rate of degradation. Biochem. J. 244: 775.PubMedGoogle Scholar
  31. 31.
    Al, Z. and Cohen, C. M. (1993) Phorbol 12-myristate 13-acetate-stimulated phosphorylation of erythrocyte membrane skeletal proteins is blocked by calpain inhibitors: possible role of protein kinase M. Biochem J. 296: 675–683.PubMedGoogle Scholar
  32. 32.
    Shea, T. B., Beermann, M. L., Griffin, W. R., Anthony, P. K., and Leli, U. (1994a) Calpain degrades the free PKC catalytic subunit (PKM) faster than intact PKC. Trans. Am. Soc. Neurochem. 25: 262.Google Scholar
  33. 33.
    Shea, T. B., Beermann, M. L., Griffin, W. R., and Leli, U. (1994b) Degradation of protein kinase Cα and its free catalytic subunit, protein kinase M, in intact human neuroblastoma cells and under cell-free conditions: Evidence that PKM is degraded by calpain-mediated proteolysis at a faster rate than PKC. FEBS Lett. 350:223.PubMedCrossRefGoogle Scholar
  34. 34.
    Shea, T. B., Cressman, C. M., Beermann, M. L., and Nixon, R. A. (1994c) Hyperphosphorylation of tau following calcium influx into human neuroblastoma: Role of calpain and PKC. Mol. Biol. Cell: 5: 168a.Google Scholar
  35. 35.
    Nixon, R. A. (1989) Calcium-activated neutral proteinases as regulators of cellular function. Implications for Alzheimer’s disease Pathogenesis. Ann. N. Y. Acad. Sci. 568: 198–208.PubMedCrossRefGoogle Scholar
  36. 36.
    Hoshi, M., Nishida, E., Miyata, Y., Sakai, H., Miyoshi, T, Ogawara, H. and Akiyama, T. (1987) Protein kinase C phosphorylates tau and induces its functional alterations. FEBS Lett. 217: 237–241.PubMedCrossRefGoogle Scholar
  37. 37.
    Steiner, B., Mandelkow, E.-M., Biernat, J., Gustke, N., Meyer, H. E., Schmidt, B., Mieskes, G., Söling, H. D., Dreschsei, D., Kirschner, M. W., Goedert, M., and Mandelkow, E. (1990) Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2+-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J. 9:3539–3544.PubMedGoogle Scholar
  38. 38.
    Shea TB. (1990) Neuritogenesis in mouse NB2a/d1 neuroblastoma cells: Triggering by calcium influx and involvement of actin and tubulin dynamics. Cell Biol Internat Reports 14:967–79.CrossRefGoogle Scholar
  39. 39.
    Shea TB, Cressman CM, Spencer MJ, Beermann ML and Nixon RA (1995) Enhancement of neurite outgrowth following calpain inhibition is mediated by protein kinase C. J Neurochem 65: 967 in press.Google Scholar
  40. 40.
    Spencer MJ and Tidball JG (1992) Calpain concentration is elevated although net calcium-dependent proteolysis is suppressed in dystrophin-deficient muscle. Exp Cell Res 203: 107–114.PubMedCrossRefGoogle Scholar
  41. 41.
    Uemori T, Shimojo T, Asada K, Asano T, Kimizuka F, Kato I, Maki M, Hatanaka M, Murachi T, Hanzawa H (1990) Characterization of a functional domain of human calpastatin. Biochem Biophys Res Comm 166: 1485–1493.PubMedCrossRefGoogle Scholar
  42. 42.
    Shea TB and Beermann ML (1991b) A method for phospholipid-mediated delivery of specific antibodies into adherent cultured cells. Biotechniques 10: 288–291.PubMedGoogle Scholar
  43. 43.
    Parker P, Coussens L, Totty N, Rhee L, Young S, Chen E, Stabel S, Waterfield M, Ullrich A (1986): The Complete Primary Structure of Protein Kinase C-the Major Phorbol Ester Receptor. Science 233:853–859.PubMedCrossRefGoogle Scholar
  44. 44.
    Vitto A. and Nixon R.A. (1986). Calcium-activated neurtral proteases of human brain: subunit structure and enzymatic properties of multiple molecular forms. J. Neurochem. 47, 1039–1051.PubMedCrossRefGoogle Scholar
  45. 45.
    Kosik KS, Orecchio LD, Binder L, Trojanowski JQ, Lee VM-Y, and Lee G (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1: 817–825.PubMedCrossRefGoogle Scholar
  46. 46.
    Samis J.A., Zboril G. and Elce J.S. (1987). Calpain I remains intact and intracellular during platelet activation. Biochem. J. 246, 481–488.PubMedGoogle Scholar
  47. 47.
    Shea TB, Beermann ML and Nixon RA (1991) Multiple proteases regulate neurite outgrowth in NB2a/d1 neuroblastoma. J Neurochem 56:842–851.PubMedCrossRefGoogle Scholar
  48. 48.
    Matsuo, E. S., Shin, R.-W., Billingsley, M. L., Van deVoorde, A., O’Connor, M., Trojanowski, J. Q. and Lee, V. M.-Y. (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13: 989–1002.PubMedCrossRefGoogle Scholar
  49. 49.
    Pope, W. B., Enam, S. A., Bawa, N., Miller, B. E., Ghanbari, H. A., and Klein, W. L. (1993) Phosphorylated tau epitope of Alzheimer’s disease is coupled to axon development in the avian central nervous system. Exp. Neurol. 120: 106–113.PubMedCrossRefGoogle Scholar
  50. 50.
    Pope, W. B., Lambert, M. P., Leypold, B., Seupaul, R., Sletten, L., Krafft, G., and Klein, W. L. (1994) Microtubule-associated protein tau is hyperphosphorylated during mitosis in the human neuroblastoma cell line SH-SY-5Y. Exp. Neurol. 126: 185–194.PubMedCrossRefGoogle Scholar
  51. 51.
    Nishizuka, Y. (1989) Studies and prospectives of the protein kinase C family for cellular regulation. Cancer 63: 1892–1903.PubMedCrossRefGoogle Scholar
  52. 52.
    Leli, U., Shea, T. B., Cataldo, A., Hauser, G., Grynspan, F., Beermann, M. L., Liepkalns, V. A., Nixon, R. A, and Parker, P. A. (1993) Differential expression and subcellular localization of protein kinase C α,β,δ,ε and γ isoforms in SH-SY-5Y neuroblastoma cells: Modifications during differentiation. J. Neurochem. 60:289–298.PubMedCrossRefGoogle Scholar
  53. 53.
    Shea TB, Beermann ML, Nixon RA. (1992b) Microtubule-associated protein tau is required for axonal neurite elaboration by neuroblastoma cells. J Neurosci Res. 32:363–374.PubMedCrossRefGoogle Scholar
  54. 54.
    Lee, J. H., Goedert, M., Hill, W. D., Lee. V. M.-Y., and Trojanowski, J. Q. (1993) Tau proteins are abnormally expressed in olfactory epithelium of Alzheimer’s disease and developmentally regulated in fetal spinal cord. Exp. Neurol. 121: 93–105.PubMedCrossRefGoogle Scholar
  55. 55.
    Mattson MP (1991) Evidence for the involvement of protein kinase C in neurodegenerative changes in cultured human cortical neurons. Exp Neurol 112:95–103.PubMedCrossRefGoogle Scholar
  56. 56.
    Nixon RA, Saito K-I, Grynspan F, Griffin WR, Katayama S, Honda T, Mohan PS, Shea TB, Beermann ML. (1994) The calcium-activated neurotral proteinase (calpain) system in aging and Alzheimer’s disease. Ann NY Acad Sci 747:77–91.PubMedCrossRefGoogle Scholar
  57. 57.
    Johnson GVW, Jope RS and Binder LI (1989) Proteolysis of tau by calpain. Biochem Biophys Res Commun 163: 1505–1511.PubMedCrossRefGoogle Scholar
  58. 58.
    Johnson GVW and Foley VG (1993) Calpain-mediated proteolysis of microtubule-associated protein 2 (MAP2) is inhibited by phosphorylation by cAMP-dependent protein kinase, but not by Ca2+/calmodulin-dependent protein kinase EL J Neurosci Res 34: 642–647.PubMedCrossRefGoogle Scholar
  59. 59.
    Litersky JM, Scott CW and Johnson GVW (1993) Phosphorylation, calpain proteolysis and tubulin binding of recombinant human tau isoforms. Brain Res 604: 32–40.PubMedCrossRefGoogle Scholar
  60. 60.
    Lang, D., Hauser, G. H., Cressman, C. M, Mohan, P. S., Nixon, R. A., and Shea, T. B. (1995) Lipids inhibit mM calpain-mediated proteolysis of PKC in vitro. J. Neurochem., 64, 25a.Google Scholar
  61. 61.
    Singh TJ, Zaidi T, Grundke-Iqbal I and Iqbal K(1995) Modulation of GSK-3-catalyzed phosphorylation of microtubule-associated protein tau by non-proline-dependent protein kinases. FEBS Lett 358:4–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Thomas B. Shea
    • 1
    • 2
  • John J. Boyce
    • 1
    • 2
  • Corrine M. Cressman
    • 1
  1. 1.Center for Cellular Neurobiology and Neurodegeneration ResearchUniversity of Massachusetts at LowellLowellUSA
  2. 2.Department of Biological SciencesUniversity of Massachusetts at LowellLowellUSA

Personalised recommendations