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Journal of Biomedicine and Biotechnology
Volume 2006 (2006), Article ID 31825, 11 pages
http://dx.doi.org/10.1155/JBB/2006/31825
Review Article

Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease: A Therapeutic Target

Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA

Received 8 November 2005; Revised 12 December 2005; Accepted 3 January 2006

Copyright © 2006 Cheng-Xin Gong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. G G Glenner and C W Wong, “Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein,” Biochemical and Biophysical Research Communications, vol. 120, no. 3, pp. 885–890, 1984. View at Publisher · View at Google Scholar
  2. C L Masters, G Simms, N A Weinman, et al., “Amyloid plaque core protein in Alzheimer disease and Down syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 12, pp. 4245–4249, 1985. View at Publisher · View at Google Scholar
  3. I Grundke-Iqbal, K Iqbal, M Quinlan, et al., “Microtubule-associated protein tau. A component of Alzheimer paired helical filaments,” The Journal of Biological Chemistry, vol. 261, no. 13, pp. 6084–6089, 1986.
  4. I Grundke-Iqbal, K Iqbal, Y C Tung, et al., “Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 13, pp. 4913–4917, 1986. View at Publisher · View at Google Scholar
  5. B E Tomlinson, G Blessed, and M Roth, “Observations on the brains of demented old people,” Journal of the Neurological Sciences, vol. 11, no. 3, pp. 205–242, 1970. View at Publisher · View at Google Scholar
  6. I Alafuzoff, K Iqbal, H Friden, R Adolfsson, and B Winblad, “Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis,” Acta Neuropathologica (Berl), vol. 74, no. 3, pp. 209–225, 1987. View at Publisher · View at Google Scholar
  7. D W Dickson, J Farlo, P Davies, et al., “Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques,” The American Journal of Pathology, vol. 132, no. 1, pp. 86–101, 1988.
  8. P V Arriagada, J H Growdon, E T Hedley-Whyte, et al., “Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease,” Neurology, vol. 42, no. 3 pt 1, pp. 631–639, 1992.
  9. K P Riley, D A Snowdon, and W R Markesbery, “Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study,” Annals of Neurology, vol. 51, no. 5, pp. 567–577, 2002. View at Publisher · View at Google Scholar
  10. D Yancopoulou and M G Spillantini, “Tau protein in familial and sporadic diseases,” Neuromolecular Medicine, vol. 4, no. 1-2, pp. 37–48, 2003. View at Publisher · View at Google Scholar
  11. K Iqbal, C Alonso Adel, S Chen, et al., “Tau pathology in Alzheimer disease and other tauopathies,” Biochimica et Biophysica Acta, vol. 1739, no. 2-3, pp. 198–210, 2005.
  12. M Hutton, C L Lendon, P Rizzu, et al., “Association of missense and 5-splice-site mutations in tau with the inherited dementia FTDP-17,” Nature, vol. 393, no. 6686, pp. 702–705, 1998. View at Publisher · View at Google Scholar
  13. P Poorkaj, T D Bird, E Wijsman, et al., “Tau is a candidate gene for chromosome 17 frontotemporal dementia,” Annals of Neurology, vol. 43, no. 6, pp. 815–825, 1998. View at Publisher · View at Google Scholar
  14. M G Spillantini, J R Murrell, M Goedert, et al., “Mutation in the tau gene in familial multiple system tauopathy with presenile dementia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 13, pp. 7737–7741, 1998. View at Publisher · View at Google Scholar
  15. K Iqbal, I Grundke-Iqbal, T Zaidi, et al., “Defective brain microtubule assembly in Alzheimer's disease,” Lancet, vol. 2, no. 8504, pp. 421–426, 1986. View at Publisher · View at Google Scholar
  16. C Alonso Adel, T Zaidi, I Grundke-Iqbal, et al., “Role of abnormally phosphorylated τ in the breakdown of microtubules in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 12, pp. 5562–5566, 1994. View at Publisher · View at Google Scholar
  17. C Alonso Adel, T Zaidi, M Novak, et al., “Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6923–6928, 2001. View at Publisher · View at Google Scholar
  18. C Alonso Adel, T Zaidi, M Novak, et al., “Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein,” The Journal of Biological Chemistry, vol. 276, no. 41, pp. 37967–37973, 2001. View at Publisher · View at Google Scholar
  19. C Alonso Adel, A Mederlyova, M Novak, et al., “Promotion of hyperphosphorylation by frontotemporal dementia tau mutations,” The Journal of Biological Chemistry, vol. 279, no. 33, pp. 34873–34881, 2004. View at Publisher · View at Google Scholar
  20. J J Lucas, F Hernandez, P Gomez-Ramos, et al., “Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice,” The EMBO Journal, vol. 20, no. 1-2, pp. 27–39, 2001. View at Publisher · View at Google Scholar
  21. M Perez, F Hernandez, A Gomez-Ramos, et al., “Formation of aberrant phosphotau fibrillar polymers in neural cultured cells,” European Journal of Biochemistry, vol. 269, no. 5, pp. 1484–1489, 2002. View at Publisher · View at Google Scholar
  22. T Fath, J Eidenmuller, and R Brandt, “Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease,” The Journal of Neuroscience, vol. 22, no. 22, pp. 9733–9741, 2002.
  23. G R Jackson, M Wiedau-Pazos, T K Sang, et al., “Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila,” Neuron, vol. 34, no. 4, pp. 509–519, 2002. View at Publisher · View at Google Scholar
  24. N H Stemberger, L A Sternberger, and J Ulrich, “Aberrant neurofilament phosphorylation in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, pp. 4274–4276, 1985. View at Publisher · View at Google Scholar
  25. L Ulloa, E M de Garcini, P Gòmez-Ramos, et al., “Microtubule-associated protein MAP1B showing a fetal phosphorylation pattern is present in sites of neurofibrillary degeneration in brains of Alzheimer's disease patients,” Molecular Brain Research, vol. 26, no. 1-2, pp. 113–122, 1994. View at Publisher · View at Google Scholar
  26. S Vijayan, E El-Akkad, I Grundke-Iqbal, et al., “A pool of β-tubulin is hyperphosphorylated at serine residues in Alzheimer disease brain,” FEBS Letters, vol. 509, no. 3, pp. 375–381, 2001. View at Publisher · View at Google Scholar
  27. J-Z Wang, Y C Tung, Y Wang, et al., “Hyperphosphorylation and accumulation of neurofilament proteins in Alzheimer disease brain and in okadaic acid-treated SY5Y cells,” FEBS Letters, vol. 507, no. 1, pp. 81–87, 2001. View at Publisher · View at Google Scholar
  28. M D Weingarten, A H Lockwood, S-Y Hwo, et al., “A protein factor essential for microtubule assembly,” Proceedings of the National Academy of Sciences of the United States of America, vol. 72, no. 5, pp. 1858–1862, 1975. View at Publisher · View at Google Scholar
  29. V M Lee, B J Balin, L Jr Otvos, and J Q Trojanowski, “A68: a major subunit of paired helical filaments and derivatized forms of normal Tau,” Science, vol. 251, no. 4994, pp. 675–678, 1991. View at Publisher · View at Google Scholar
  30. R L Neve, P Harris, K S Kosik, 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 Research, vol. 387, no. 3, pp. 271–280, 1986.
  31. M Goedert, M G Spillantini, R Jakes, et al., “Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease,” Neuron, vol. 3, no. 4, pp. 519–526, 1989. View at Publisher · View at Google Scholar
  32. G Lee, R L Neve, and K S Kosik, “The microtubule binding domain of tau protein,” Neuron, vol. 2, no. 6, pp. 1615–1624, 1989. View at Publisher · View at Google Scholar
  33. B L Goode and S C Feinstein, “Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau,” The Journal of Cell Biology, vol. 124, no. 5, pp. 769–782, 1994. View at Publisher · View at Google Scholar
  34. D Panda, B L Goode, S C Feinstein, et al., “Kinetic stabilization of microtubule dynamics at steady state by tau and microtubule-binding domains of tau,” Biochemistry, vol. 34, no. 35, pp. 11117–11127, 1995. View at Publisher · View at Google Scholar
  35. N Hirokawa, Y Shiomura, and S Okabe, “Tau proteins: the molecular structure and mode of binding on microtubules,” The Journal of Cell Biology, vol. 107, no. 4, pp. 1449–1459, 1988. View at Publisher · View at Google Scholar
  36. R Brandt, J Leger, and G Lee, “Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain,” The Journal of Cell Biology, vol. 131, no. 5, pp. 1327–1340, 1995. View at Publisher · View at Google Scholar
  37. M A Utton, G M Gibb, I D Burdett, et al., “Functional differences of tau isoforms containing 3 or 4 C-terminal repeat regions and the influence of oxidative stress,” The Journal of Biological Chemistry, vol. 276, no. 36, pp. 34288–34297, 2001. View at Publisher · View at Google Scholar
  38. P M Stanford, C E Shepherd, G M Halliday, et al., “Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia,” Brain, vol. 126, no. pt 4, pp. 814–826, 2003. View at Publisher · View at Google Scholar
  39. K S Kosik, L D Orecchio, S Bakalis, et al., “Developmentally regulated expression of specific tau sequences,” Neuron, vol. 2, no. 4, pp. 1389–1397, 1989. View at Publisher · View at Google Scholar
  40. M Goedert and R Jakes, “Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization,” The EMBO Journal, vol. 9, no. 13, pp. 4225–4230, 1990.
  41. Y Tatebayashi, N Haque, Y C Tung, et al., “Role of tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport,” Journal of Cell Science, vol. 117, no. pt 9, pp. 1653–1663, 2004. View at Publisher · View at Google Scholar
  42. A Ebneth, R Godemann, K Stamer, et al., “Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease,” The Journal of Cell Biology, vol. 143, no. 3, pp. 777–794, 1998. View at Publisher · View at Google Scholar
  43. T Ishihara, M Hong, B Zhang, et al., “Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform,” Neuron, vol. 24, no. 3, pp. 751–762, 1999. View at Publisher · View at Google Scholar
  44. K Spittaels, C Van den Haute, J Van Dorpe, et al., “Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein,” The American Journal of Pathology, vol. 155, no. 6, pp. 2153–2165, 1999.
  45. J Lewis, E McGowan, J Rockwood, et al., “Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein,” Nature Genetics, vol. 25, no. 4, pp. 402–405, 2000. View at Publisher · View at Google Scholar
  46. A Probst, J Gotz, K H Wiederhold, et al., “Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein,” Acta Neuropathologica (Berl), vol. 99, no. 5, pp. 469–481, 2000. View at Publisher · View at Google Scholar
  47. A Rendon, D Jung, and V Jancsik, “Interaction of microtubules and microtubule-associated proteins (MAPs) with rat brain mitochondria,” The Biochemical Journal, vol. 269, no. 2, pp. 555–556, 1990.
  48. T Kampers, P Friedhoff, J Biernat, et al., “RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments,” FEBS Letters, vol. 399, no. 3, pp. 344–349, 1996. View at Publisher · View at Google Scholar
  49. Q Hua, R Q He, N Haque, et al., “Microtubule associated protein tau binds to double-stranded but not single-stranded DNA,” Cellular and Molecular Life Sciences, vol. 60, no. 2, pp. 413–421, 2003. View at Publisher · View at Google Scholar
  50. G Lee, S T Newman, D L Gard, H Band, and G Panchamoorthy, “Tau interacts with src-family non-receptor tyrosine kinases,” Journal of Cell Science, vol. 111, no. pt 21, pp. 3167–3177, 1998.
  51. K Bhaskar, S-H Yen, and G Lee, “Disease-related modifications in tau affect the interaction between Fyn and Tau,” The Journal of Biological Chemistry, vol. 280, no. 42, pp. 35119–35125, 2005. View at Publisher · View at Google Scholar
  52. A Jaspert, R Fahsold, H Grehl, et al., “Myotonic dystrophy: correlation of clinical symptoms with the size of the CTG trinucleotide repeat,” Journal of Neurology, vol. 242, no. 2, pp. 99–104, 1995. View at Publisher · View at Google Scholar
  53. S M Jenkins and G V Johnson, “Tau complexes with phospholipase C-gamma in situ,” NeuroReport, vol. 9, no. 1, pp. 67–71, 1998.
  54. D W Cleveland, S Y Hwo, and M W Kirschner, “Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly,” Journal of Molecular Biology, vol. 116, no. 2, pp. 227–247, 1977. View at Publisher · View at Google Scholar
  55. G Lindwall and R D Cole, “Phosphorylation affects the ability of tau protein to promote microtubule assembly,” The Journal of Biological Chemistry, vol. 259, no. 8, pp. 5301–5305, 1984.
  56. H Ksiezak-Reding, W K Liu, S H Yen, et al., “Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments,” Brain Research, vol. 597, no. 2, pp. 209–219, 1992. View at Publisher · View at Google Scholar
  57. E Köpke, Y-C Tung, S Shaikh, et al., “Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease,” The Journal of Biological Chemistry, vol. 268, no. 32, pp. 24374–24384, 1993.
  58. A Kenessey and S H Yen, “The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments,” Brain Research, vol. 629, no. 1, pp. 40–46, 1993. View at Publisher · View at Google Scholar
  59. E S Matsuo, R W Shin, M L Billingsley, et al., “Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau,” Neuron, vol. 13, no. 4, pp. 989–1002, 1994. View at Publisher · View at Google Scholar
  60. T D Garver, K A Harris, R A Lehman, et al., “Tau phosphorylation in human, primate, and rat brain: evidence that a pool of tau is highly phosphorylated in vivo and is rapidly dephosphorylated in vitro,” Journal of Neurochemistry, vol. 63, no. 6, pp. 2279–2287, 1994.
  61. K Iqbal, T Zaidi, C Bancher, et al., “Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation,” FEBS Letters, vol. 349, no. 1, pp. 104–108, 1994. View at Publisher · View at Google Scholar
  62. D N Drechsel, A A Hyman, M H Cobb, and M W Kirschner, “Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau,” Molecular Biology of the Cell, vol. 3, no. 10, pp. 1141–1154, 1992.
  63. G T Bramblett, M Goedert, R Jakes, et al., “Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding,” Neuron, vol. 10, no. 6, pp. 1089–1099, 1993. View at Publisher · View at Google Scholar
  64. H Yoshida and Y Ihara, “Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau,” Journal of Neurochemistry, vol. 61, no. 3, pp. 1183–1186, 1993. View at Publisher · View at Google Scholar
  65. J Biernat, N Gustke, G Drewes, et al., “Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding,” Neuron, vol. 11, no. 1, pp. 153–163, 1993. View at Publisher · View at Google Scholar
  66. C Alonso Adel, I Grundke-Iqbal, and K Iqbal, “Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules,” Nature Medicine, vol. 2, no. 7, pp. 783–787, 1996. View at Publisher · View at Google Scholar
  67. J-Z Wang, C-X Gong, T Zaidi, et al., “Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B,” The Journal of Biological Chemistry, vol. 270, no. 9, pp. 4854–4860, 1995. View at Publisher · View at Google Scholar
  68. J-Z Wang, I Grundke-Iqbal, and K Iqbal, “Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease,” Nature Medicine, vol. 2, no. 8, pp. 871–875, 1996. View at Publisher · View at Google Scholar
  69. C-X Gong, T Lidsky, J Wegiel, et al., “Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease,” The Journal of Biological Chemistry, vol. 275, no. 8, pp. 5535–5544, 2000. View at Publisher · View at Google Scholar
  70. S Khatoon, I Grundke-Iqbal, and K Iqbal, “Brain levels of microtubule-associated protein tau are elevated in Alzheimer's disease: a radioimmuno-slot-blot assay for nanograms of the protein,” Journal of Neurochemistry, vol. 59, no. 2, pp. 750–753, 1992. View at Publisher · View at Google Scholar
  71. S Khatoon, I Grundke-Iqbal, and K Iqbal, “Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains,” FEBS Letters, vol. 351, no. 1, pp. 80–84, 1994. View at Publisher · View at Google Scholar
  72. R Kohnken, K Buerger, R Zinkowski, et al., “Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer's disease patients,” Neuroscience Letters, vol. 287, no. 3, pp. 187–190, 2000. View at Publisher · View at Google Scholar
  73. K Ishiguro, H Ohno, H Arai, et al., “Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease,” Neuroscience Letters, vol. 270, no. 2, pp. 91–94, 1999. View at Publisher · View at Google Scholar
  74. H Hampel, K Buerger, R Kohnken, et al., “Tracking of Alzheimer's disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231,” Annals of Neurology, vol. 49, no. 4, pp. 545–546, 2001. View at Publisher · View at Google Scholar
  75. H Hampel, K Buerger, R Zinkowski, et al., “Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study,” Archives of General Psychiatry, vol. 61, no. 1, pp. 95–102, 2004. View at Publisher · View at Google Scholar
  76. L Parnetti, A Lanari, S Amici, et al., “CSF phosphorylated tau is a possible marker for discriminating Alzheimer's disease from dementia with Lewy bodies,” Neurological Sciences, vol. 22, no. 1, pp. 77–78, 2001. View at Publisher · View at Google Scholar
  77. E Vanmechelen, E Van Kerschaver, K Blennow, et al., “CSF-phospho-tau (181P) as a promising marker for discriminating Alzheimer's disease from dementia with Lewy bodies,” in Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics, K Iqbal, S Sissodia, and B Winblad, Eds., pp. 285–291, John Wiley & Sons, Chichester, UK, 2001.
  78. N Itoh, H Arai, K Urakami, et al., “Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease,” Annals of Neurology, vol. 50, no. 2, pp. 150–156, 2001. View at Publisher · View at Google Scholar
  79. Y Y Hu, S S He, X C Wang, et al., “Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay,” The American Journal of Pathology, vol. 160, no. 4, pp. 1269–1278, 2002.
  80. K Buerger, R Zinkowski, S J Teipel, et al., “Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231,” Archives of Neurology, vol. 59, no. 8, pp. 1267–1272, 2002. View at Publisher · View at Google Scholar
  81. M Goedert, M G Spillantini, N J Cairns, et al., “Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms,” Neuron, vol. 8, no. 1, pp. 159–168, 1992. View at Publisher · View at Google Scholar
  82. C-X Gong, F Liu, I Grundke-Iqbal, et al., “Post-translational modifications of tau protein in Alzheimer's disease,” Journal of Neural Transmission, vol. 112, no. 6, pp. 813–838, 2005. View at Publisher · View at Google Scholar
  83. C-X Gong, T J Singh, I Grundke-Iqbal, et al., “Phosphoprotein phosphatase activities in Alzheimer disease brain,” Journal of Neurochemistry, vol. 61, no. 3, pp. 921–927, 1993. View at Publisher · View at Google Scholar
  84. C-X Gong, S Shaikh, J-Z Wang, T Zaidi, et al., “Phosphatase activity toward abnormally phosphorylated τ: decrease in Alzheimer disease brain,” Journal of Neurochemistry, vol. 65, no. 2, pp. 732–738, 1995.
  85. V Vogelsberg-Ragaglia, T Schuck, J Q Trojanowski, et al., “PP2A mRNA expression is quantitatively decreased in Alzheimer's disease hippocampus,” Experimental Neurology, vol. 168, no. 2, pp. 402–412, 2001. View at Publisher · View at Google Scholar
  86. J F Loring, X Wen, J M Lee, et al., “A gene expression profile of Alzheimer's disease,” DNA and Cell Biology, vol. 20, no. 11, pp. 683–695, 2001. View at Publisher · View at Google Scholar
  87. E Sontag, A Luangpirom, C Hladik, et al., “Altered expression levels of the protein phosphatase 2A ABαC enzyme are associated with Alzheimer disease pathology,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 4, pp. 287–301, 2004.
  88. F Liu, I Grundke-Iqbal, K Iqbal, et al., “Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation,” The European Journal of Neuroscience, vol. 22, no. 8, pp. 1942–1950, 2005. View at Publisher · View at Google Scholar
  89. F Liu, K Iqbal, I Grundke-Iqbal, et al., “Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease,” The Journal of Biological Chemistry, vol. 280, no. 3, pp. 1790–1796, 2005. View at Publisher · View at Google Scholar
  90. R Hoffmann, V M Lee, S Leight, et al., “Unique Alzheimer's disease paired helical filament specific epitopes involve double phosphorylation at specific sites,” Biochemistry, vol. 36, no. 26, pp. 8114–8124, 1997. View at Publisher · View at Google Scholar
  91. M Hasegawa, R Jakes, R Crowther, et al., “Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein,” FEBS Letters, vol. 384, no. 1, pp. 25–30, 1996. View at Publisher · View at Google Scholar
  92. T Bussiere, P R Hof, C Mailliot, et al., “Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration,” Acta Neuropathologica (Berl), vol. 97, no. 3, pp. 221–230, 1999. View at Publisher · View at Google Scholar
  93. G Lee, R Thangavel, V M Sharma, et al., “Phosphorylation of tau by fyn: implications for Alzheimer's disease,” The Journal of Neuroscience, vol. 24, no. 9, pp. 2304–2312, 2004. View at Publisher · View at Google Scholar
  94. R Williamson, T Scales, B R Clark, et al., “Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-β peptide exposure: involvement of Src family protein kinases,” The Journal of Neuroscience, vol. 22, no. 1, pp. 10–20, 2002.
  95. P Derkinderen, T M Scales, D P Hanger, et al., “Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase,” The Journal of Neuroscience, vol. 25, no. 28, pp. 6584–6593, 2005. View at Publisher · View at Google Scholar
  96. M Rapoport, H N Dawson, L I Binder, et al., “Tau is essential to beta -amyloid-induced neurotoxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 9, pp. 6364–6369, 2002. View at Publisher · View at Google Scholar
  97. J Brich, F S Shie, B W Howell, et al., “Genetic modulation of tau phosphorylation in the mouse,” The Journal of Neuroscience, vol. 23, no. 1, pp. 187–192, 2003.
  98. V MY Lee, M Goedert, and J Q Trojanowski, “Neurodegenerative tauopathies,” Annual Review of Neuroscience, vol. 24, pp. 1121–1159, 2001. View at Publisher · View at Google Scholar
  99. C Bancher, C Brunner, H Lassman, et al., “Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease,” Brain Research, vol. 477, no. 1-2, pp. 90–99, 1989. View at Publisher · View at Google Scholar
  100. C Bancher, I Grundke-Iqbal, K Iqbal, et al., “Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease,” Brain Research, vol. 539, no. 1, pp. 11–18, 1991. View at Publisher · View at Google Scholar
  101. E Braak, H Braak, and E-M Mandelkow, “A sequence of cytoskeletal changes related to the formation of neurofibrillary tangles and neuropil threads,” Acta Neuropathologica, vol. 87, pp. 544–567, 1994.
  102. A Sengupta, J Kabat, M Novak, et al., “Maximal inhibition of tau binding to microtubules requires the phosphorylation of tau at both Thr 231 and Ser 262,” Neurobiology of Aging, vol. 19S, pp. S124–S524, 1998.
  103. A Schneider, J Biernat, M von Bergen, et al., “Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments,” Biochemistry, vol. 38, no. 12, pp. 3549–3558, 1999. View at Publisher · View at Google Scholar
  104. A Abraha, N Ghoshal, T C Gamblin, et al., “C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease,” Journal of Cell Science, vol. 113, no. pt 21, pp. 3737–3745, 2000.
  105. C Haase, J Stieler, T Arendt, et al., “Pseudophosphorylation of tau protein alters its ability for self-aggregation,” Journal of Neurochemistry, vol. 88, no. 6, pp. 1509–1520, 2004.
  106. A Ferrari, F Hoerndli, T Baechi, et al., “Beta-amyloid induces paired helical filament-like tau filaments in tissue culture,” The Journal of Biological Chemistry, vol. 278, no. 41, pp. 40162–40168, 2003. View at Publisher · View at Google Scholar
  107. A Harada, K Oguchi, S Okabe, et al., “Altered microtubule organization in small-calibre axons of mice lacking tau protein,” Nature, vol. 369, no. 6480, pp. 488–491, 1994. View at Publisher · View at Google Scholar
  108. C Alonso Adel, I Grundke-Iqbal, H S Barra, et al., “Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 1, pp. 298–303, 1997. View at Publisher · View at Google Scholar
  109. F Hernandez, J Borrell, C Guaza, et al., “Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments,” Journal of Neurochemistry, vol. 83, no. 6, pp. 1529–1533, 2002. View at Publisher · View at Google Scholar
  110. V MY Lee, T K Kenyon, and J Q Trojanowski, “Transgenic animal models of tauopathies,” Biochimica et Biophysica Acta, vol. 1739, no. 2-3, pp. 251–259, 2005.
  111. R Kayed, E Head, J L Thompson, et al., “Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis,” Science, vol. 300, no. 5618, pp. 486–489, 2003. View at Publisher · View at Google Scholar
  112. A Sanbe, H Osinska, C Villa, et al., “Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 38, pp. 13592–13597, 2005. View at Publisher · View at Google Scholar
  113. L F Lau, J B Schachter, P A Seymour, et al., “Tau protein phosphorylation as a therapeutic target in Alzheimer's disease,” Current Topics in Medicinal Chemistry, vol. 2, no. 4, pp. 395–415, 2002. View at Publisher · View at Google Scholar
  114. Q Tian and J Wang, “Role of serine/threonine protein phosphatase in Alzheimer's disease,” Neurosignals, vol. 11, no. 5, pp. 262–269, 2002. View at Publisher · View at Google Scholar
  115. G V Johnson and W H Stoothoff, “Tau phosphorylation in neuronal cell function and dysfunction,” Journal of Cell Science, vol. 117, no. pt 24, pp. 5721–5729, 2004. View at Publisher · View at Google Scholar
  116. M Goedert, R Jakes, Z Qi, et al., “Protein phosphatase 2A is the major enzyme in brain that dephosphorylates tau protein phosphorylated by proline-directed protein kinases or cyclic AMP-dependent protein kinase,” Journal of Neurochemistry, vol. 65, no. 6, pp. 2804–2807, 1995.
  117. E Sontag, V Nunbhakdi-Craig, G Lee, et al., “Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A,” Neuron, vol. 17, no. 6, pp. 1201–1207, 1996. View at Publisher · View at Google Scholar
  118. E Sontag, V Nunbhakdi-Craig, G Lee, et al., “Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies,” The Journal of Biological Chemistry, vol. 274, no. 36, pp. 25490–25498, 1999. View at Publisher · View at Google Scholar
  119. M Bennecib, C-X Gong, I Grundke-Iqbal, et al., “Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain,” FEBS Letters, vol. 485, no. 1, pp. 87–93, 2000. View at Publisher · View at Google Scholar
  120. S Kins, A Crameri, D R Evans, et al., “Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice,” The Journal of Biological Chemistry, vol. 276, no. 41, pp. 38193–38200, 2001.
  121. F Liu, I Grundke-Iqbal, K Iqbal, et al., “Truncation and activation of calcineurin A by calpain l in Alzheimer disease brain,” The Journal of Biological Chemistry, vol. 280, no. 45, pp. 37755–37762, 2005. View at Publisher · View at Google Scholar
  122. A Sengupta, Q Wu, I Grundke-Iqbal, et al., “Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5,” Molecular and Cellular Biochemistry, vol. 167, no. 1-2, pp. 99–105, 1997. View at Publisher · View at Google Scholar
  123. J-Z Wang, Q Wu, A Smith, et al., “τ is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase,” FEBS Letters, vol. 436, no. 1, pp. 28–34, 1998. View at Publisher · View at Google Scholar
  124. S J Liu, J Y Zhang, H L Li, et al., “Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain ,” The Journal of Biological Chemistry, vol. 279, no. 48, pp. 50078–50088, 2004. View at Publisher · View at Google Scholar
  125. J H Cho and G V Johnson, “Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding,” The Journal of Biological Chemistry, vol. 278, no. 1, pp. 187–193, 2003. View at Publisher · View at Google Scholar
  126. J H Cho and G V Johnson, “Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau's ability to bind and stabilize microtubules,” Journal of Neurochemistry, vol. 88, no. 2, pp. 349–358, 2004.
  127. L Sun, X Wang, S Liu, et al., “Bilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat,” FEBS Letters, vol. 579, no. 1, pp. 251–258, 2005. View at Publisher · View at Google Scholar
  128. S J Liu, A H Zhang, H L Li, et al., “Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory,” Journal of Neurochemistry, vol. 87, no. 6, pp. 1333–1344, 2003.
  129. L Baki, J Shioi, P Wen, et al., “PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations,” The EMBO Journal, vol. 23, no. 13, pp. 2586–2596, 2004. View at Publisher · View at Google Scholar
  130. X Li, F Lu, Q Tian, et al., “Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture,” Journal of Neural Transmission, vol. 113, no. 1, pp. 93–102, 2006. View at Publisher · View at Google Scholar
  131. Y Q Deng, G G Xu, P Duan, et al., “Effects of melatonin on wortmannin-induced tau hyperphosphorylation,” Acta Pharmacologica Sinica, vol. 26, no. 5, pp. 519–526, 2005. View at Publisher · View at Google Scholar
  132. G N Patrick, L Zukerberg, M Nikolic, et al., “Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration,” Nature, vol. 402, no. 6762, pp. 615–622, 1999. View at Publisher · View at Google Scholar
  133. B C Yoo and G Lubec, “p25 protein in neurodegeneration,” Nature, vol. 411, no. 6839, pp. 763–764, 2001. View at Publisher · View at Google Scholar
  134. S Taniguchi, Y Fujita, S Hayashi, et al., “Calpain-mediated degradation of p35 to p25 in postmortem human and rat brains,” FEBS Letters, vol. 489, no. 1, pp. 46–50, 2001. View at Publisher · View at Google Scholar
  135. K C Nguyen, J L Rosales, M Barboza, et al., “Controversies over p25 in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 4, no. 2, pp. 123–126, 2002.
  136. A Tandon, H Yu, L Wang, et al., “Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles,” Journal of Neurochemistry, vol. 86, no. 3, pp. 572–581, 2003. View at Publisher · View at Google Scholar
  137. T Tanaka, J Zhong, K Iqbal, et al., “The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases,” FEBS Letters, vol. 426, no. 2, pp. 248–254, 1998. View at Publisher · View at Google Scholar
  138. M Bennecib, C-X Gong, I Grundke-Iqbal, et al., “Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356,” FEBS Letters, vol. 490, no. 1-2, pp. 15–22, 2001. View at Publisher · View at Google Scholar
  139. J-J Pei, C-X Gong, W An, et al., “Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease,” The American Journal of Pathology, vol. 163, no. 3, pp. 845–858, 2003.
  140. S Kins, P Kurosinski, R M Nitsch, and J Gotz, “Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice,” The American Journal of Pathology, vol. 163, no. 3, pp. 833–843, 2003.
  141. W-L An, R F Cowburn, L Li, et al., “Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease,” The American Journal of Pathology, vol. 163, no. 2, pp. 591–607, 2003.
  142. H Tanimukai, I Grundke-Iqbal, and K Iqbal, “Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease,” The American Journal of Pathology, vol. 166, no. 6, pp. 1761–1771, 2005.
  143. C S Arnold, G V Johnson, R N Cole, et al., “The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine,” The Journal of Biological Chemistry, vol. 271, no. 46, pp. 28741–28744, 1996. View at Publisher · View at Google Scholar
  144. T Lefebvre, S Ferreira, L Dupont-Wallois, et al., “Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins—a role in nuclear localization,” Biochimica et Biophysica Acta, vol. 1619, no. 2, pp. 167–176, 2003.
  145. F Liu, K Iqbal, I Grundke-Iqbal, et al., “O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 29, pp. 10804–10809, 2004. View at Publisher · View at Google Scholar
  146. F I Comer and G W Hart, “O-Glycosylation of nuclear and cytosolic proteins. Dynamic interplay between O-GlcNAc and O-phosphate,” The Journal of Biological Chemistry, vol. 275, no. 38, pp. 29179–29182, 2002. View at Publisher · View at Google Scholar
  147. L A Robertson, K L Moya, and K C Breen, “The potential role of tau protein O-glycosylation in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 6, no. 5, pp. 489–495, 2004.
  148. C-X Gong, F Liu, I Grundke-Iqbal, et al., “Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation,” Journal of Alzheimer's Disease. 2006; in press.
  149. M Takahishi, Y Tsumioka, T Yamada, et al., “Glycosylation of microtubule-associated protein tau in Alzheimer's disease brain,” Acta Neuropathologica (Berl), vol. 97, no. 6, pp. 635–641, 1999. View at Publisher · View at Google Scholar
  150. F Liu, T Zaidi, I Grundke-Iqbal, et al., “Role of glycosylation in hyperphosphorylation of tau in Alzheimer's disease,” FEBS Letters, vol. 512, no. 1–3, pp. 101–106, 2002. View at Publisher · View at Google Scholar
  151. F Liu, T Zaidi, I Grandke-Iqbal, et al., “Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5,” Neuroscience, vol. 115, no. 3, pp. 829–837, 2002. View at Publisher · View at Google Scholar
  152. F Liu, I Grundke-Iqbal, K Iqbal, et al., “Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3β,” FEBS Letters, vol. 530, no. 1–3, pp. 209–214, 2002. View at Publisher · View at Google Scholar
  153. B Winblad and N Poritis, “Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine),” International Journal of Geriatric Psychiatry, vol. 14, no. 2, pp. 135–146, 1999. View at Publisher · View at Google Scholar
  154. B Reisberg, A Doody, and A Stoffler, “Memantine in moderate-to-severe Alzheimer's disease,” The New England Journal of Medicine, vol. 348, no. 14, pp. 1333–1341, 2003. View at Publisher · View at Google Scholar
  155. L Li, A Sengupta, N Haque, et al., “Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration,” FEBS Letters, vol. 566, no. 1–3, pp. 261–269, 2004. View at Publisher · View at Google Scholar
  156. S P Li, Y Q Deng, Y P Wang, et al., “Melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity,” Journal of Pineal Research, vol. 36, no. 3, pp. 186–191, 2004. View at Publisher · View at Google Scholar
  157. X C Li, Z F Wang, J X Zhang, et al., “Effect of melatonin on calyculin A-induced tau hyperphosphorylation,” European Journal of Pharmacology, vol. 510, no. 1-2, pp. 25–30, 2005. View at Publisher · View at Google Scholar
  158. L Q Zhu, S H Wang, Z Q Ling, et al., “Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat,” Journal of Pineal Research, vol. 37, no. 2, pp. 71–77, 2004. View at Publisher · View at Google Scholar
  159. D L Wang, Z Q Ling, F Y Cao, et al., “Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain,” Journal of Pineal Research, vol. 37, no. 1, pp. 11–16, 2004. View at Publisher · View at Google Scholar