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Medicine » Mental and Behavioural Disorders and Diseases of the Nervous System » "Understanding Alzheimer's Disease", book edited by Inga Zerr, ISBN 978-953-51-1009-5, Published: February 27, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 5

Phosphorylation of Tau Protein Associated as a Protective Mechanism in the Presence of Toxic, C-Terminally Truncated Tau in Alzheimer's Disease

By José Luna-Muñoz, Charles R. Harrington, Claude M. Wischik, Paola Flores-Rodríguez, Jesús Avila, Sergio R. Zamudio, Fidel De la Cruz, Raúl Mena, Marco A. Meraz-Ríos and Benjamin Floran-Garduño
DOI: 10.5772/54228

  1. Arnold, S.E., et al., The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cerebral cortex, 1991. 1(1): p. 103-16.

  2. Arriagada, P.V., et al., Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology, 1992. 42(3 Pt 1): p. 631-9.

  3. Garcia-Sierra, F., et al., The extent of neurofibrillary pathology in perforant pathway neurons is the key determinant of dementia in the very old. Acta Neuropathol, 2000. 100(1): p. 29-35.

  4. Braak, H. and E. Braak, Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol, 1991. 82(4): p. 239-59.

  5. Braak, H., et al., Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol, 2006. 112(4): p. 389-404.

  6. Kidd, M., Paired helical filaments in electron microscopy of Alzheimer's disease. Nature, 1963. 197: p. 192-3.

  7. Wischik, C.M., et al., Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A, 1988. 85(13): p. 4884-8.

  8. Crowther, R.A. and C.M. Wischik, Image reconstruction of the Alzheimer paired helical filament. Embo J, 1985. 4(13B): p. 3661-5.

  9. Kondo, J., et al., The carboxyl third of tau is tightly bound to paired helical filaments. Neuron, 1988. 1(9): p. 827-34.

  10. Lee, G., R.L. Neve, and K.S. Kosik, The microtubule binding domain of tau protein. Neuron, 1989. 2(6): p. 1615-24.

  11. Perry, G., et al., Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci U S A, 1987. 84(9): p. 3033-6.

  12. Mori, H., J. Kondo, and Y. Ihara, Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science, 1987. 235(4796): p. 1641-4.

  13. Ledesma, M.D., P. Bonay, and J. Avila, Tau protein from Alzheimer's disease patients is glycated at its tubulin-binding domain. J Neurochem, 1995. 65(4): p. 1658-64.

  14. Ledesma, M.D., et al., Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem, 1994. 269(34): p. 21614-9.

  15. Wang, J.Z., I. Grundke-Iqbal, and K. Iqbal, Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease. Nat Med, 1996. 2(8): p. 871-5.

  16. Horiguchi, T., et al., Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol, 2003. 163(3): p. 1021-31.

  17. Tucholski, J., J. Kuret, and G.V. Johnson, Tau is modified by tissue transglutaminase in situ: possible functional and metabolic effects of polyamination. J Neurochem, 1999. 73(5): p. 1871-80.

  18. Alonso, A.C., I. Grundke-Iqbal, and K. Iqbal, Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med, 1996. 2(7): p. 783-7.

  19. Alonso Adel, C., et al., Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc Natl Acad Sci U S A, 2006. 103(23): p. 8864-9.

  20. Novak, M., J. Kabat, and C.M. Wischik, Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. Embo J, 1993. 12(1): p. 365-70.

  21. Wischik, C.M., et al., Quantitative analysis of tau protein in paired helical filament preparations: implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer's disease. Neurobiol Aging, 1995. 16(3): p. 409-17; discussion 418-31.

  22. Wischik, C.M., et al., Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A, 1988. 85(12): p. 4506-10.

  23. Novak, M., Truncated tau protein as a new marker for Alzheimer's disease. Acta Virol, 1994. 38(3): p. 173-89.

  24. Novak, M., et al., Difference between the tau protein of Alzheimer paired helical filament core and normal tau revealed by epitope analysis of monoclonal antibodies 423 and 7.51. Proc Natl Acad Sci U S A, 1991. 88(13): p. 5837-41.

  25. Guillozet-Bongaarts, A.L., et al., Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease. Neurobiol Aging, 2005. 26(7): p. 1015-22.

  26. Garcia-Sierra, F., et al., Conformational changes and truncation of tau protein during tangle evolution in Alzheimer's disease. J Alzheimers Dis, 2003. 5(2): p. 65-77.

  27. Garcia-Sierra, F., S. Mondragon-Rodriguez, and G. Basurto-Islas, Truncation of tau protein and its pathological significance in Alzheimer's disease. J Alzheimers Dis, 2008. 14(4): p. 401-9.

  28. Alonso, A., et al., Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A, 2001. 98(12): p. 6923-8.

  29. Iqbal, K. and I. Grundke-Iqbal, Discoveries of tau, abnormally hyperphosphorylated tau and others of neurofibrillary degeneration: a personal historical perspective. J Alzheimers Dis, 2006. 9(3 Suppl): p. 219-42.

  30. Augustinack, J.C., et al., Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease. Acta Neuropathol, 2002. 103(1): p. 26-35.

  31. Novak, M., et al., Characterisation of the first monoclonal antibody against the pronase resistant core of the Alzheimer PHF. Prog Clin Biol Res, 1989. 317: p. 755-61.

  32. Garcia-Sierra, F., et al., Accumulation of C-terminally truncated tau protein associated with vulnerability of the perforant pathway in early stages of neurofibrillary pathology in Alzheimer's disease. J Chem Neuroanat, 2001. 22(1-2): p. 65-77.

  33. Wischik, C.M., Lay R.Y., Harrington C.R. , Modelling prion-like processing of tau protein in Alzheimer´s disease for pharmaceutical development., in Modifications in Alzheimer´s disease, B.R. Avila J., Kosik K.S., Editor 1997, Harwood Academic: Amsterdam. p. 185-241.

  34. Guillozet-Bongaarts, A.L., et al., Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J Neurochem, 2006. 97(4): p. 1005-14.

  35. Schneider, A., et al., Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry, 1999. 38(12): p. 3549-58.

  36. Arendt, T., et al., Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci, 2003. 23(18): p. 6972-81.

  37. Su, B., et al., Physiological regulation of tau phosphorylation during hibernation. J Neurochem, 2008. 105(6): p. 2098-108.

  38. Doherty, G.J. and H.T. McMahon, Mediation, modulation, and consequences of membrane-cytoskeleton interactions. Annu Rev Biophys, 2008. 37: p. 65-95.

  39. Morris, M., et al., The many faces of tau. Neuron, 2011. 70(3): p. 410-26.

  40. Weingarten, M.D., et al., A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A, 1975. 72(5): p. 1858-62.

  41. Witman, G.B., et al., Tubulin requires tau for growth onto microtubule initiating sites. Proc Natl Acad Sci U S A, 1976. 73(11): p. 4070-4.

  42. Harada, A., et al., Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature, 1994. 369(6480): p. 488-91.

  43. Dixit, R., et al., Differential regulation of dynein and kinesin motor proteins by tau. Science, 2008. 319(5866): p. 1086-9.

  44. Caceres, A. and K.S. Kosik, Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature, 1990. 343(6257): p. 461-3.

  45. Neve, R.L., et al., 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, 1986. 387(3): p. 271-80.

  46. Mandelkow, E.M., et al., Structure, microtubule interactions, and phosphorylation of tau protein. Ann N Y Acad Sci, 1996. 777: p. 96-106.

  47. Heicklen-Klein, A. and I. Ginzburg, Tau promoter confers neuronal specificity and binds Sp1 and AP-2. J Neurochem, 2000. 75(4): p. 1408-18.

  48. Andreadis, A., et al., A tau promoter region without neuronal specificity. J Neurochem, 1996. 66(6): p. 2257-63.

  49. Drubin, D., et al., Regulation of microtubule protein levels during cellular morphogenesis in nerve growth factor-treated PC12 cells. J Cell Biol, 1988. 106(5): p. 1583-91.

  50. Vila-Ortiz, G.J., et al., The rate of Tau synthesis is differentially regulated during postnatal development in mouse cerebellum. Cell Mol Neurobiol, 2001. 21(5): p. 535-43.

  51. David, D.C., et al., Proteasomal degradation of tau protein. J Neurochem, 2002. 83(1): p. 176-85.

  52. Delobel, P., et al., Proteasome inhibition and Tau proteolysis: an unexpected regulation. FEBS Lett, 2005. 579(1): p. 1-5.

  53. Dickey, C.A., et al., The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest, 2007. 117(3): p. 648-58.

  54. Min, S.W., et al., Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron, 2010. 67(6): p. 953-66.

  55. Kenessey, A., et al., Degradation of tau by lysosomal enzyme cathepsin D: implication for Alzheimer neurofibrillary degeneration. J Neurochem, 1997. 69(5): p. 2026-38.

  56. Wang, Y., et al., Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet, 2009. 18(21): p. 4153-70.

  57. Mena, R., et al., Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer's disease. Acta Neuropathol, 1996. 91(6): p. 633-41.

  58. Mena R., L.-M.J., Stages of pathological tau-protein processing in Alzheimer´s disease: From soluble aggregation to polymetization into insoluble tau-PHFs, in Currents Hypotheses and Research Milestones, R.B.M.a.G. Perry, Editor 2009. p. 79-91.

  59. Fasulo, L., Visintin M., Novak M., Cattaneo A., Tau truncation in Alzheimer´s disease: encompassing PHF core tau induces apoptosis ina COS cells. Alzheimes´s reports, 1998. 1: p. 25-32.

  60. Wischik, C.M., et al., Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proceedings of the National Academy of Sciences of the United States of America, 1996. 93(20): p. 11213-8.

  61. Mena, R., et al., Monitoring pathological assembly of tau and beta-amyloid proteins in Alzheimer's disease. Acta Neuropathol, 1995. 89(1): p. 50-6.

  62. Fasulo, L., et al., The neuronal microtubule-associated protein tau is a substrate for caspase-3 and an effector of apoptosis. J Neurochem, 2000. 75(2): p. 624-33.

  63. Gamblin, T.C., et al., Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A, 2003. 100(17): p. 10032-7.

  64. Rissman, R.A., et al., Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest, 2004. 114(1): p. 121-30.

  65. Gamblin, T.C., et al., In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants. Biochemistry, 2000. 39(20): p. 6136-44.

  66. Horowitz, P.M., et al., N-terminal fragments of tau inhibit full-length tau polymerization in vitro. Biochemistry, 2006. 45(42): p. 12859-66.

  67. Luna-Munoz, J., et al., Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease. J Alzheimers Dis, 2007. 12(4): p. 365-75.

  68. Castellani, R.J., et al., Phosphorylated tau: toxic, protective, or none of the above. J Alzheimers Dis, 2008. 14(4): p. 377-83.

  69. Nelson, P.T., H. Braak, and W.R. Markesbery, Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. Journal of neuropathology and experimental neurology, 2009. 68(1): p. 1-14.

  70. Abner, E.L., et al., "End-stage" neurofibrillary tangle pathology in preclinical Alzheimer's disease: fact or fiction? Journal of Alzheimer's disease : JAD, 2011. 25(3): p. 445-53.

  71. Lee, H.G., et al., Tau phosphorylation in Alzheimer's disease: pathogen or protector? Trends Mol Med, 2005. 11(4): p. 164-9.

  72. Cash, A.D., et al., Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Am J Pathol, 2003. 162(5): p. 1623-7.

  73. Paula-Barbosa, M., M.A. Tavares, and A. Cadete-Leite, A quantitative study of frontal cortex dendritic microtubules in patients with Alzheimer's disease. Brain research, 1987. 417(1): p. 139-42.

  74. Yuan, A., et al., Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci, 2008. 28(7): p. 1682-7.

  75. Leroy, K., et al., Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice. Am J Pathol, 2007. 171(3): p. 976-92.

  76. Jicha, G.A., et al., A conformation- and phosphorylation-dependent antibody recognizing the paired helical filaments of Alzheimer's disease. J Neurochem, 1997. 69(5): p. 2087-95.

  77. McMillan, P.J., et al., Truncation of tau at E391 promotes early pathologic changes in transgenic mice. Journal of neuropathology and experimental neurology, 2011. 70(11): p. 1006-19.

  78. Morsch, R., W. Simon, and P.D. Coleman, Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol, 1999. 58(2): p. 188-97.

  79. Guo, H., et al., Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. Am J Pathol, 2004. 165(2): p. 523-31.

  80. Lassmann, H., et al., Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ. Acta Neuropathol, 1995. 89(1): p. 35-41.

  81. Kudo, W., et al., Inhibition of Bax protects neuronal cells from oligomeric Abeta neurotoxicity. Cell death & disease, 2012. 3: p. e309.

  82. Li, H.L., et al., Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proc Natl Acad Sci U S A, 2007. 104(9): p. 3591-6.

  83. Luna-Munoz, J., et al., Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer's disease. J Alzheimers Dis, 2005. 8(1): p. 29-41.