Abnormal hyperphosphorylation of tau: Sites, regulation, and molecular mechanism of neurofibrillary degeneration

Advances in Alzheimer's Disease

Volumn 3, Issue , 2012, Pages 123-139

  Wang, Jian Zhi ^a   Xia, Yi Yuan ^a   Grundke Iqbal, Inge ^b   Iqbal, Khalid ^b  

^a HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY   (China)

^b NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENTAL DISABILITIES   (United States)

Author keywords

Alzheimer's disease; neurofibrillary degeneration; post translational modifications of tau; protein kinases; protein phosphatases; tau phosphorylation

Indexed keywords

PHOSPHATASE; PROTEIN KINASE; TAU PROTEIN;

ACETYLATION; AMNESIA; APOPTOSIS; ARTICLE; BRAIN NERVE CELL; CELL SURVIVAL; DEMENTIA; DISEASE ASSOCIATION; ENZYME INHIBITION; GLYCOSYLATION; HIBERNATION; HUMAN; INTRACELLULAR TRANSPORT; MICROTUBULE ASSEMBLY; MOLECULAR DYNAMICS; MOLECULAR PATHOLOGY; NEOCORTEX; NERVE DEGENERATION; NEUROFIBRILLARY TANGLE; NITRATION; NONHUMAN; PROTEIN AGGREGATION; PROTEIN DEPHOSPHORYLATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; SUMOYLATION; UBIQUITINATION;

EID: 84877980134     PISSN: 22105727     EISSN: 22105735     Source Type: Book Series    
DOI: 10.3233/978-1-61499-154-0-123     Document Type: Article

References (214)

1. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, WisniewskiHM(1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261, 6084-6089.
2. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83, 4913-4917.
3. Iqbal K, Grundke-Iqbal I, ZaidiT, Merz PA,WenGY, Shaikh SS,Wisniewski HM, Alafuzoff I,Winblad B (1986) Defective brain microtubule assembly in Alzheimer's disease. Lancet 2, 421-426.
4. Alonso AD, ZaidiT, Grundke-Iqbal I, IqbalK(1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A 91, 5562-5566.
5. Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K (1997) 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. Proc Natl Acad Sci U S A 94, 298-303.
6. Alonso AD, Grundke-Iqbal I, Iqbal K (1996) Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2, 783-787.
7. Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268, 24374-24384.
8. Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: Decrease in Alzheimer disease brain. J Neurochem 65, 732-738.
9. Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1993) Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem 61, 921-927.
10. 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.
11. Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Titani K, Ihara Y (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau. J Biol Chem 270, 823-829.
12. Hanger DP, Betts JC, Loviny TL, Blackstock WP, Anderton BH (1998) New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer's disease brain using nanoelectrospray mass spectrometry. J Neurochem 71, 2465-2476.
13. Hanger DP, Byers HL, Wray S, Leung KY, Saxton MJ, Seereeram A, Reynolds CH,WardMA,AndertonBH(2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282, 23645-23654.
14. Lindwall G, Cole RD (1984) Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 259, 5301-5305.
15. Wang JZ, Grundke-Iqbal I, IqbalK(2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25, 59-68.
16. Alonso AD, Di Clerico J, Li B, Corbo CP, Alaniz ME, Grundke-Iqbal I, Iqbal K (2010) Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J Biol Chem 285, 30851-30860.
17. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298, 1912-1934.
18. Singh TJ, Grundke-Iqbal I, McDonald B, Iqbal K (1994) Comparison of the phosphorylation of microtubuleassociated protein tau by non-proline dependent protein kinases. Mol Cell Biochem 131, 181-189.
19. Sengupta A, Kabat J, Novak M, Wu Q, Grundke-Iqbal I, Iqbal K (1998) Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357, 299-309.
20. Wang JZ, Wu Q, Smith A, Grundke-Iqbal I, Iqbal K (1998) Tau 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 Lett 436, 28-34.
21. Zheng-Fischhofer Q, Biernat J, MandelkowEM, Illenberger S, Godemann R, Mandelkow E (1998) Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical- filament-like conformation. Eur J Biochem 252, 542-552.
22. Jicha GA, O'Donnell A, Weaver C, Angeletti R, Davies P (1999) Hierarchical phosphorylation of recombinant tau by the paired-helical filament-associated protein kinase is dependent on cyclic AMP-dependent protein kinase. J Neurochem 72, 214-224.
23. Sengupta A, Wu Q, Grundke-Iqbal I, Iqbal K, Singh TJ (1997) Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5. Mol Cell Biochem 167, 99-105.
24. Singh TJ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Modulation of GSK-3-catalyzed phosphorylation of microtubuleassociated protein tau by non-proline-dependent protein kinases. FEBS Lett 358, 4-8.
25. Li T, Paudel HK (2006) Glycogen synthase kinase 3beta phosphorylates Alzheimer's disease-specific Ser396 of microtubule-associated protein tau by a sequential mechanism. Biochemistry 45, 3125-3133.
26. Cho JH, Johnson GV (2004) 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. J Neurochem 88, 349-358.
27. Liu SJ, Zhang JY, Li HL, Fang ZY, Wang Q, Deng HM, Gong CX, Grundke-Iqbal I, Iqbal K, Wang JZ (2004) Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J Biol Chem 279, 50078-50088.
28. Zhang Y, Li HL,Wang DL, Liu SJ,Wang JZ (2006) A transitory activation of protein kinase-A induces a sustained tau hyperphosphorylation at multiple sites in N2a cells-imply a new mechanism in Alzheimer pathology. J Neural Transm 113, 1487-1497.
29. Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM, Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H (2004) Phosphorylation of tau by fyn: Implications for Alzheimer's disease. J Neurosci 24, 2304-2312.
30. Kinoshita E, Kinoshita-Kikuta E, Matsubara M, Yamada S, Nakamura H, ShiroY, AokiY, Okita K,Koike T (2008) Separation of phosphoprotein isotypes having the same number of phosphate groups using phosphate-affinity SDS-PAGE. Proteomics 8, 2994-3003.
31. Lebouvier T, Scales TM, Hanger DP, Geahlen RL, Lardeux B, Reynolds CH, Anderton BH, Derkinderen P (2008) The microtubule-associated protein tau is phosphorylated by Syk. Biochim Biophys Acta 1783, 188-192.
32. Lebouvier T, Scales TM, Williamson R, Noble W, Duyckaerts C, Hanger DP, Reynolds CH, Anderton BH, Derkinderen P (2009) The microtubule-associated protein tau is also phosphorylated on tyrosine. J Alzheimers Dis 18, 1-9.
33. Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G (1998) Tau interacts with src-family non-receptor tyrosine kinases. J Cell Sci 111(Pt 21), 3167-3177.
34. Cohen PT (1997) Novel protein serine/threonine phosphatases: Variety is the spice of life. Trends Biochem Sci 22, 245-251.
35. Bastians H, Ponstingl H (1996) The novel human protein serine/threonine phosphatase 6 is a functional homologue of budding yeast Sit4p and fission yeast ppe1, which are involved in cell cycle regulation. J Cell Sci 109(Pt 12), 2865-2874.
36. Huang X, Cheng A, Honkanen RE (1997) Genomic organization of the human PP4 gene encoding a serine/threonine protein phosphatase (PP4) suggests a common ancestry with PP2A. Genomics 44, 336-343.
37. Huang X, Honkanen RE (1998) Molecular cloning, expression, and characterization of a novel human serine/threonine protein phosphatase, PP7, that is homologous to Drosophila retinal degeneration C gene product (rdgC). J Biol Chem 273, 1462-1468.
38. Skinner J, Sinclair C, Romeo C, Armstrong D, Charbonneau H, Rossie S (1997) Purification of a fatty acid-stimulated protein-serine/threonine phosphatase from bovine brain and its identification as a homolog of protein phosphatase 5. J Biol Chem 272, 22464-22471.
39. Gong CX, Grundke-Iqbal I, Damuni Z, Iqbal K (1994) Dephosphorylation of microtubule-associated protein tau by protein phosphatase-1 and -2C and its implication in Alzheimer disease. FEBS Lett 341, 94-98.
40. Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem 270, 4854-4860.
41. Wang JZ, Grundke-Iqbal I, Iqbal K (1996) Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res Mol Brain Res 38, 200-208.
42. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 22, 1942-1950.
43. LiuGP, ZhangY,Yao XQ, Zhang CE, Fang J,Wang Q,Wang JZ (2008) Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms. Neurobiol Aging 29, 1348-1358.
44. Wang X, Blanchard J, Kohlbrenner E, Clement N, Linden RM, Radu A, Grundke-Iqbal I, Iqbal K (2010) The carboxyterminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment. FASEB J 24, 4420-4432.
45. Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118, 53-69.
46. Tanimukai H, Grundke-Iqbal I, Iqbal K (2005) Upregulation of inhibitors of protein phosphatase-2A in Alzheimer's disease. Am J Pathol 166, 1761-1771.
47. Arnaud L, Chen S, Liu F, Li B, Khatoon S, Grundke-Iqbal I, Iqbal K (2011) Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I(2)(PP2A)/SET. FEBS Lett 585, 2653-2659.
48. Bolognin S, Blanchard J, Wang X, Basurto-Islas G, Tung YC, Kohlbrenner E, Grundke-Iqbal I, Iqbal K (2012) An experimental rat model of sporadic Alzheimer's disease and rescue of cognitive impairment with a neurotrophic peptide. Acta Neuropathol 123, 133-151.
49. Sontag E, Luangpirom A, Hladik C, Mudrak I, Ogris E, Speciale S, White CL 3rd (2004) Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 63, 287-301.
50. Zhou XW, Gustafsson JA, Tanila H, Bjorkdahl C, Liu R, Winblad B, Pei JJ (2008) Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis 31, 386-394.
51. Liu R, Zhou XW, Tanila H, Bjorkdahl C, Wang JZ, Guan ZZ, Cao Y, Gustafsson JA, Winblad B, Pei JJ (2008) Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology. J Cell Mol Med 12, 241-257.
52. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K (2005) Posttranslational modifications of tau protein in Alzheimer's disease. J Neural Transm 112, 813-838.
53. Robertson LA, Moya KL, Breen KC (2004) The potential role of tau protein O-glycosylation in Alzheimer's disease. J Alzheimers Dis 6, 489-495.
54. Breen KC, Coughlan CM, Hayes FD (1998) The role of glycoproteins in neural development function, and disease. Mol Neurobiol 16, 163-220.
55. Wang JZ, Grundke-Iqbal I, Iqbal K (1996) Glycosylation of microtubule-associated protein tau: An abnormal posttranslational modification in Alzheimer's disease. Nat Med 2, 871-875.
56. Arnold CS, Johnson GV, Cole RN, Dong DL, Lee M, Hart GW(1996) The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J Biol Chem 271, 28741-28744.
57. Liu F, Zaidi T, Iqbal K, Grundke-Iqbal I, Merkle RK, Gong CX (2002) Role of glycosylation in hyperphosphorylation of tau in Alzheimer's disease. FEBS Lett 512, 101-106.
58. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX (2004) O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A 101, 10804-10809.
59. Arnold CS, Cole RN, Johnson GVW, Hart GW (1994) Tau is a glycoprotein. Soc Neurosci Abst 20, 1035.
60. Torres CR, Hart GW (1984) Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J Biol Chem 259, 3308-3317.
61. Griffith LS, Schmitz B (1999) O-linked Nacetylglucosamine levels in cerebellar neurons respond reciprocally to pertubations of phosphorylation. Eur J Biochem 262, 824-831.
62. Hu P, Shimoji S, Hart GW (2010) Site-specific interplay between O-GlcNAcylation and phosphorylation in cellular regulation. FEBS Lett 584, 2526-2538.
63. Martin L, Latypova X, Terro F (2011) Post-translational modifications of tau protein: Implications for Alzheimer's disease. Neurochem Int 58, 458-471.
64. Li X, Lu F, Wang JZ, Gong CX (2006) Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting. Eur J Neurosci 23, 2078-2086.
65. Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 132, 1820-1832.
66. Lefebvre T, Ferreira S, Dupont-Wallois L, Bussiere T, Dupire MJ, Delacourte A, Michalski JC, Caillet-BoudinML (2003) Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins-a role in nuclear localization. Biochim Biophys Acta 1619, 167-176.
67. O'Donnell N, Zachara NE, Hart GW,Marth JD (2004) Ogtdependent X-chromosome-linked protein glycosylation is a requisite modification in somatic cell function and embryo viability. Mol Cell Biol 24, 1680-1690.
68. Smet-Nocca C, Broncel M, Wieruszeski JM, Tokarski C, Hanoulle X, Leroy A, Landrieu I, Rolando C, Lippens G, Hackenberger CP (2011) Identification of O-GlcNAc sites within peptides of the Tau protein and their impact on phosphorylation. Mol Biosyst 7, 1420-1429.
69. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K (2006) Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis 9, 1-12.
70. Kim EJ (2011) Chemical arsenal for the study of O-GlcNAc. Molecules 16, 1987-2022.
71. Castegna A, Thongboonkerd V, Klein JB, Lynn B, Markesbery WR, Butterfield DA (2003) Proteomic identification of nitrated proteins in Alzheimer's disease brain. J Neurochem 85, 1394-1401.
72. Good PF,Werner P, Hsu A, OlanowCW, PerlDP(1996) Evidence of neuronal oxidative damage in Alzheimer's disease. Am J Pathol 149, 21-28.
73. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997)Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 17, 2653-2657.
74. Horiguchi T, Uryu K, Giasson BI, Ischiropoulos H, Light-Foot R, Bellmann C, Richter-Landsberg C, Lee VM, Trojanowski JQ (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163, 1021-1031.
75. Reynolds MR, Berry RW, Binder LI (2005) Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: Implications for Alzheimer's disease. Biochemistry 44, 1690-1700.
76. Reynolds MR, Reyes JF, Fu Y, Bigio EH, Guillozet-Bongaarts AL, Berry RW, Binder LI (2006) Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies. J Neurosci 26, 10636-10645.
77. Reyes JF, Fu Y, Vana L, Kanaan NM, Binder LI (2011) Tyrosine nitration within the proline-rich region of Tau in Alzheimer's disease. Am J Pathol 178, 2275-2285.
78. Reyes JF, Reynolds MR, Horowitz PM, Fu Y, Guillozet-Bongaarts AL, Berry R, Binder LI (2008) A possible link between astrocyte activation and tau nitration in Alzheimer's disease. Neurobiol Dis 31, 198-208.
79. Hensley K, Maidt ML, Yu Z, Sang H, Markesbery WR, Floyd RA (1998) Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J Neurosci 18, 8126-8132.
80. Tohgi H, Abe T, Yamazaki K, Murata T, Ishizaki E, Isobe C (1999) Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease. Neurosci Lett 269, 52-54.
81. Zhang YJ, Xu YF, Liu YH, Yin J, Li HL, Wang Q, Wang JZ (2006) Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms. FASEB J 20, 1431-1442.
82. Zhang YJ, Xu YF, Liu YH, Yin J, Wang JZ (2005) Nitric oxide induces tau hyperphosphorylation via glycogen synthase kinase-3beta activation. FEBS Lett 579, 6230-6236.
83. Reynolds MR, Berry RW, Binder LI (2005) Site-specific nitration differentially influences tau assembly in vitro. Biochemistry 44, 13997-14009.
84. Zilka N, Filipcik P, Koson P, Fialova L, Skrabana R, Zilkova M, Rolkova G, Kontsekova E, Novak M (2006) Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 580, 3582-3588.
85. Kovacech B, Novak M (2010) Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer's disease. Curr Alzheimer Res 7, 708-716.
86. Zilkova M, Zilka N, Kovac A, Kovacech B, Skrabana R, Skrabanova M, NovakM(2011) Hyperphosphorylated truncated protein tau induces caspase-3 independent apoptosislike pathway in the Alzheimer's disease cellular model. J Alzheimers Dis 23, 161-169.
87. Novak M, Kabat J, Wischik CM (1993) Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. EMBO J 12, 365-370.
88. McMillan PJ, Kraemer BC, Robinson L, Leverenz JB, Raskind M, Schellenberg G (2011) Truncation of tau at E391 promotes early pathologic changes in transgenic mice. J Neuropathol Exp Neurol 70, 1006-1019.
89. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL (2003) Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A 100, 10032-10037.
90. Guillozet-Bongaarts AL, Cahill ME, Cryns VL, Reynolds MR, Berry RW, Binder LI (2006) Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: In vitro evidence and implications for tangle formation in vivo. J Neurochem 97, 1005-1014.
91. Cho JH, Johnson GV (2004) Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ. J Biol Chem 279, 54716-54723.
92. Basurto-Islas G, Luna-Munoz J, Guillozet-Bongaarts AL, Binder LI, Mena R, Garcia-Sierra F (2008) Accumulation of aspartic acid421- and glutamic acid391-cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease. J Neuropathol Exp Neurol 67, 470-483.
93. Gamblin TC, Berry RW, Binder LI (2003) Tau polymerization: Role of the amino terminus. Biochemistry 42, 2252-2257.
94. Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, Lee VM (2011) The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun 2, 252.
95. Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L (2011) Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953-966.
96. Dorval V, Fraser PE (2006) Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem 281, 9919-9924.
97. Takahashi K, Ishida M, Komano H, Takahashi H (2008) SUMO-1 immunoreactivity co-localizes with phospho-Tau in APP transgenic mice but not in mutant tau transgenic mice. Neurosci Lett 441, 90-93.
98. Dorval V, Fraser PE (2007) SUMO on the road to neurodegeneration. Biochim Biophys Acta 1773, 694-706.
99. Perry G, Friedman R, Shaw G, Chau V (1987) Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci U S A 84, 3033-3036.
100. Biernat J, Gustke N, Drewes G, Mandelkow EM, 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.
101. Sengupta A, Novak M, Grundke-Iqbal I, Iqbal K (2006) Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level. FEBS Lett 580, 5925-5933.
102. Dudek SM, Johnson GV (1993) Transglutaminase catalyzes the formation of sodium dodecyl sulfate-insoluble, Alz-50-reactive polymers of tau. J Neurochem 61, 1159-1162.
103. Wilhelmus MM, Grunberg SC, Bol JG, van Dam AM, Hoozemans JJ, Rozemuller AJ, Drukarch B (2009) Transglutaminases and transglutaminase-catalyzed cross-links colocalize with the pathological lesions in Alzheimer's disease brain. Brain Pathol 19, 612-622.
104. Johnson GV, Cox TM, Lockhart JP, Zinnerman MD, Miller ML, Powers RE (1997) Transglutaminase activity is increased in Alzheimer's disease brain. Brain Res 751, 323-329.
105. Zhang W, Johnson BR, Suri DE, Martinez J, Bjornsson TD (1998) Immunohistochemical demonstration of tissue transglutaminase in amyloid plaques. Acta Neuropathol 96, 395-400.
106. Citron BA, Suo Z, SantaCruz K, Davies PJ, Qin F, Festoff BW (2002) Protein crosslinking, tissue transglutaminase, alternative splicing and neurodegeneration. Neurochem Int 40, 69-78.
107. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 98, 6923-6928.
108. Braak H, Braak E, Grundke-Iqbal I, Iqbal K (1986) Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: A third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci Lett 65, 351-355.
109. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: A follow-up study. Lancet Neurol 5, 228-234.
110. Hampel H, Burger K, Pruessner JC, Zinkowski R, DeBernardis J,Kerkman D, Leinsinger G, EvansAC,Davies P, Moller HJ, Teipel SJ (2005) Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch Neurol 62, 770-773.
111. Alonso AD, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K (2004) Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 279, 34873-34881.
112. Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F (2005) Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem 280, 3963-3973.
113. Boekhoorn K, Terwel D, Biemans B, Borghgraef P,Wiegert O, Ramakers GJ, De Vos K, Krugers H, Tomiyama T, Mori H, Joels M, van Leuven F, Lucassen PJ (2006) Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci 26, 3514-3523.
114. Schindowski K, Bretteville A, Leroy K, Begard S, Brion JP, Hamdane M, Buee L (2006) Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169, 599-616.
115. Duff K, Planel E (2005) Untangling memory deficits. Nat Med 11, 826-827.
116. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, YueM, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476-481.
117. Sun L, Liu SY, Zhou XW, Wang XC, Liu R, Wang Q, Wang JZ (2003) Inhibition of protein phosphatase 2Aand protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats. Neuroscience 118, 1175-1182.
118. Sun L,Wang X, Liu S,Wang Q,Wang J, Bennecib M, Gong CX, Sengupta A, Grundke-Iqbal I, Iqbal K (2005) Bilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat. FEBS Lett 579, 251-258.
119. Feinstein SC, Wilson L (2005) Inability of tau to properly regulate neuronal microtubule dynamics:Aloss-of-function mechanism by which tau might mediate neuronal cell death. Biochim Biophys Acta 1739, 268-279.
120. Salehi A, Delcroix JD, Mobley WC (2003) Traffic at the intersection of neurotrophic factor signaling and neurodegeneration. Trends Neurosci 26, 73-80.
121. Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: Implications for Alzheimer's disease. J Cell Biol 143, 777-794.
122. Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156, 1051-1063.
123. Yang Y, Yang XF, Wang YP, Tian Q, Wang XC, Li HL, Wang Q,Wang JZ (2007) Inhibition of protein phosphatases induces transport deficits and axonopathy. J Neurochem 102, 878-886.
124. Spittaels K, Van Den Haute C, Van Dorpe J, Bruynseels K, Vandezande K, Laenen I, Geerts H, Mercken M, Sciot R, Van Lommel A, Loos R, Van Leuven F (1999) Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol 155, 2153-2165.
125. Cripps D, Thomas SN, Jeng Y, Yang F, Davies P, Yang AJ (2006) Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J Biol Chem 281, 10825-10838.
126. Mori H, Kondo J, Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235, 1641-1644.
127. Keller JN, Hanni KB, MarkesberyWR(2000) Impaired proteasome function in Alzheimer's disease. J Neurochem 75, 436-439.
128. Keck S, Nitsch R, Grune T, Ullrich O (2003) Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease. J Neurochem 85, 115-122.
129. Ren QG, Liao XM, Chen XQ, Liu GP, Wang JZ (2007) Effects of tau phosphorylation on proteasome activity. FEBS Lett 581, 1521-1528.
130. Ren QG, Liao XM, Wang ZF, Qu ZS, Wang JZ (2006) The involvement of glycogen synthase kinase-3 and protein phosphatase-2A in lactacystin-induced tau accumulation. FEBS Lett 580, 2503-2511.
131. Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res 477, 90-99.
132. Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, Geschwind DH (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34, 509-519.
133. Chau KW, Chan WY, Shaw PC, Chan HY (2006) Biochemical investigation of Tau protein phosphorylation status and its solubility properties in Drosophila. Biochem Biophys Res Commun 346, 150-159.
134. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 102, 6990-6995.
135. Perez M, Hernandez F, Lim F, Diaz-Nido J, Avila J (2003) Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis 5, 301-308.
136. Avila J, Santa-Maria I, Perez M, Hernandez F, Moreno F (2006) Tau phosphorylation, aggregation, and cell toxicity. J Biomed Biotechnol 2006, 74539.
137. Morsch R, SimonW, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58, 188-197.
138. Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, Atzori C, Migheli A, Crowther RA, Ghetti B, Spillantini MG, Goedert M(2002)Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22, 9340-9351.
139. Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT (2006) Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 168, 1598-1607.
140. Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25, 5446-5454.
141. Alonso AD, Li B, Grundke-Iqbal I, IqbalK(2006) Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc Natl Acad Sci U S A 23, 8864-8869.
142. Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM (2007) Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci U S A 104, 10252-10257.
143. Khlistunova I, Biernat J,Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM (2006) Inducible expression of Tau repeat domain in cell models of tauopathy: Aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 281, 1205-1214.
144. Cash AD, Aliev G, Siedlak SL, Nunomura A, Fujioka H, Zhu X, Raina AK, Vinters HV, Tabaton M, Johnson AB, Paula-Barbosa M, Avila J, Jones PK, Castellani RJ, Smith MA, Perry G (2003) Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation. Am J Pathol 162, 1623-1627.
145. Iliev AI, Ganesan S, Bunt G,Wouters FS (2006) Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity. J Biol Chem 281, 37195-37204.
146. Le Corre S, Klafki HW, Plesnila N, Hubinger G, Obermeier A, Sahagun H, Monse B, Seneci P, Lewis J, Eriksen J, Zehr C, YueM,McGowan E, Dickson DW, Hutton M, RoderHM (2006) An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc Natl Acad Sci U S A 103, 9673-9678.
147. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van Der Zee EA, Harkany T, Holzer M, Hartig W (2003) Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 23, 6972-6981.
148. Zhou F, Zhu X, Castellani RJ, Stimmelmayr R, Perry G, Smith MA, Drew KL (2001) Hibernation, a model of neuroprotection. Am J Pathol 158, 2145-2151.
149. Planel E, MiyasakaT, LauneyT, Chui DH,Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A (2004) Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: Implications for Alzheimer's disease. J Neruosci 24, 2401-2411.
150. Run X, Liang Z, Zhang L, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Anesthesia induces phosphorylation of tau. J Alzheimers Dis 16, 619-626.
151. Raina AK, Hochman A, Ickes H, Zhu X, Ogawa O, Cash AD, Shimohama S, Perry G, Smith MA (2003) Apoptotic promoters and inhibitors in Alzheimer's disease: Who wins out? Prog Neuropsychopharmacol Biol Psychiatry 27, 251-254.
152. Hardy J (2006) Has the amyloid cascade hypothesis for Alzheimer's disease been proved? Curr Alzheimer Res 3, 71-73.
153. Liu XA, Liao K, Liu R, Wang HH, Zhang Y, Zhang Q, Wang Q, Li HL, Tian Q, Wang JZ (2010) Tau dephosphorylation potentiates apoptosis by mechanisms involving a failed dephosphorylation/activation of Bcl-2. J Alzheimers Dis 19, 953-962.
154. Liu GP, Wei W, Zhou X, Zhang Y, Shi HH, Yin J, Yao XQ, Peng CX, Hu J,Wang Q, Li HL,Wang JZ (2012) I(2) (PP2A) regulates p53 and Akt correlatively and leads the neurons to abort apoptosis. Neurobiol Aging 33, 254-264.
155. Wang ZF,Yin J, ZhangY, Zhu LQ, Tian Q,Wang XC, Li HL, Wang JZ (2010) Overexpression of tau proteins antagonizes amyloid-beta-potentiated apoptosis through mitochondriacaspase-3 pathway in N2a cells. J Alzheimers Dis 20, 145-157.
156. Wang HH, Li HL, Liu R, Zhang Y, Liao K, Wang Q, Wang JZ, Liu SJ (2010) Tau overexpression inhibits cell apoptosis with the mechanisms involving multiple viability-related factors. J Alzheimers Dis 21, 167-179.
157. Rametti A, Esclaire F, Yardin C, Terro F (2004) Linking alterations in tau phosphorylation and cleavage during neuronal apoptosis. J Biol Chem 279, 54518-54528.
158. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20, 27-39.
159. Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F (2004) Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci 24, 6021-6027.
160. Amadoro G, Serafino AL, Barbato C, Ciotti MT, Sacco A, Calissano P, Canu N (2004) Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons. Cell Death Differ 11, 217-230.
161. Grundke-Iqbal I, Iqbal K, Tung YC, Wang GP, Wisniewski HM (1985) Alzheimer paired helical filaments: Cross-reacting polypeptide/s normally present in brain. Acta Neuropathol (Berl) 66, 52-61.
162. Iqbal K, Zaidi T, Bancher C, Grundke-Iqbal I (1994) Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Lett 349, 104-108.
163. Iqbal K, Grundke-Iqbal I, Smith AJ, George L, Tung YC, ZaidiT(1989) Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease. Proc Natl Acad Sci U S A 86, 5646-5650.
164. Goedert M, Jakes R, Crowther RA, Six J, Lubke U, Vandermeeren M, Cras P, Trojanowski JQ, Lee VM (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A 90, 5066-5070.
165. Porzig R, Singer D, Hoffmann R (2007) Epitope mapping of mAbs AT8 and Tau5 directed against hyperphosphorylated regions of the human tau protein. Biochem Biophys Res Commun 358, 644-649.
166. Pei JJ, Grundke-Iqbal I, Iqbal K, Bogdanovic N, Winblad B, Cowburn RF (1998) Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer's disease neurofibrillary degeneration. Brain Res 797, 267-277.
167. Singh TJ, Zaidi T, Grundke-Iqbal I, Iqbal K (1996) Nonproline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain. Mol Cell Biochem 154, 143-151.
168. Goedert M, Jakes R, Crowther RA, Cohen P, Vanmechelen E, Vandermeeren M, Cras P (1994) Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer's disease: Identification of phosphorylation sites in tau protein. Biochem J 301(Pt 3), 871-877.
169. Seubert P, Mawal-Dewan M, Barbour R, Jakes R, Goedert M, Johnson GV, Litersky JM, Schenk D, Lieberburg I, Trojanowski JQ, et al. (1995) Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau. J Biol Chem 270, 18917-18922.
170. Otvos L Jr, Feiner L, Lang E, Szendrei GI, Goedert M, Lee VM (1994) Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. J Neurosci Res 39, 669-673.
171. Zemlan FP, Dean GE (1996) Monoclonal antibody PHF-9 recognizes phosphorylated serine 404 of tau protein and labels paired helical filaments. J Neurosci Res 46, 90-97.
172. Hasegawa M, Jakes R, Crowther RA, Lee VM, Ihara Y, GoedertM(1996) Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein. FEBS Lett 384, 25-30.
173. Ikura Y, Kudo T, Tanaka T, Tanii H, Grundke-Iqbal I, Iqbal K, Takeda M (1998) Levels of tau phosphorylation at different sites in Alzheimer disease brain. Neuroreport 9, 2375-2379.
174. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33, 95-130.
175. Derkinderen P, Scales TM, Hanger DP, Leung KY, Byers HL, Ward MA, Lenz C, Price C, Bird IN, Perera T, Kellie S,Williamson R, NobleW,Van Etten RA, LeroyK, Brion JP, Reynolds CH, Anderton BH (2005) Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J Neurosci 25, 6584-6593.
176. Hanger DP, Byers HL, Wray S, Leung KY, Saxton MJ, Seereeram A, Reynolds CH,WardMA,AndertonBH(2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282, 23645-23654.
177. Scott CW, Spreen RC, Herman JL, Chow FP, Davison MD, Young J, Caputo CB (1993) Phosphorylation of recombinant tau by cAMP-dependent protein kinase. Identification of phosphorylation sites and effect on microtubule assembly. J Biol Chem 268, 1166-1173.
178. Litersky JM, Johnson GV, Jakes R, Goedert M, Lee M, Seubert P (1996) Tau protein is phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulindependent protein kinase II within its microtubule-binding domains at Ser-262 and Ser-356. Biochem J 316(Pt 2), 655-660.
179. Sironi JJ, Yen SH, Gondal JA, Wu Q, Grundke-Iqbal I, Iqbal K (1998) Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. FEBS Lett 436, 471-475.
180. Schneider A, Biernat J, von Bergen M, Mandelkow E, Mandelkow EM (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38, 3549-3558.
181. Wang J,Wang X, Liu R,Wang Q, Grundke-Iqbal I, Iqbal K (2002) In vitro analysis of tau phosphorylation sites and its biological activity. Chin Med Sci J 17, 13-16.
182. Ksiezak-Reding H, Pyo HK, Feinstein B, Pasinetti GM (2003) Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta 1639, 159-168.
183. Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, Hashimoto T, Terashima A, Nakai M, Mori H, Ono Y, Tanaka C (2001) Phosphorylation of tau is regulated by PKN. J Biol Chem 276, 10025-10031.
184. Virdee K,Yoshida H, Peak-ChewS, GoedertM(2007) Phosphorylation of human microtubule-associated protein tau by protein kinases of the AGC subfamily. FEBS Lett 581, 2657-2662.
185. Pei JJ, An WL, ZhouXW, Nishimura T, Norberg J, Benedikz E, Gotz J, Winblad B (2006) P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS Lett 580, 107-114.
186. Amano M, Kaneko T, Maeda A, Nakayama M, Ito M, Yamauchi T, Goto H, FukataY, Oshiro N, Shinohara A, Iwamatsu A, Kaibuchi K (2003) Identification of tau and MAP2 as novel substrates of Rho-kinase and myosin phosphatase. J Neurochem 87, 780-790.
187. Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, Meyer HE, Mandelkow EM, Mandelkow E (1995) Microtubule-associated protein/microtubule affinityregulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J Biol Chem 270, 7679-7688.
188. Singh TJ, Grundke-Iqbal I, Wu WQ, Chauhan V, Novak M, Kontzekova E, Iqbal K (1997) Protein kinase C and calcium/calmodulin-dependent protein kinase II phosphorylate three-repeat and four-repeat tau isoforms at different rates. Mol Cell Biochem 168, 141-148.
189. Singh TJ,Wang JZ,NovakM,KontzekovaE, Grundke-Iqbal I, Iqbal K (1996) Calcium/calmodulin-dependent protein kinase II phosphorylates tau at Ser-262 but only partially inhibits its binding to microtubules.FEBSLett 387, 145-148.
190. Thornton C, Bright NJ, Sastre M, Muckett PJ, Carling D (2011) AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure. Biochem J 434, 503-512.
191. Vingtdeux V, Davies P, Dickson DW, Marambaud P (2011) AMPK is abnormally activated in tangle- and pretangle-bearing neurons in Alzheimer's disease and other tauopathies. Acta Neuropathol 121, 337-349.
192. Yoshida H, Goedert M (2011) Phosphorylation of microtubule-associated protein tau by AMPK-related kinases. J Neurochem 120, 165-176.
193. Singh TJ, Grundke-Iqbal I, Iqbal K (1995) Phosphorylation of tau protein by casein kinase-1 converts it to an abnormal Alzheimer-like state. J Neurochem 64, 1420-1423.
194. Sato S, Cerny RL, Buescher JL, Ikezu T (2006) Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation. J Neurochem 98, 1573-1584.
195. Tomizawa K, Omori A, Ohtake A, Sato K, Takahashi M (2001) Tau-tubulin kinase phosphorylates tau at Ser-208 and Ser-210, sites found in paired helical filament-tau. FEBS Lett 492, 221-227.
196. Liu F, Iqbal K, Grundke-Iqbal I, Gong CX (2002) Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3beta. FEBS Lett 530, 209-214.
197. Wang JZ, Liu F (2008) Microtubule-associated protein tau in development, degeneration, and protection of neurons. Prog Neurobiol 85, 148-175.
198. Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K,Winblad B, Cowburn RF (2001) Localization of active forms of Cjun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. J Alzheimers Dis 3, 41-48.
199. Yoshida H, Hastie CJ, McLauchlan H, Cohen P, Goedert M (2004) Phosphorylation of microtubule-associated protein tau by isoforms of c-Jun N-terminal kinase (JNK). J Neurochem 90, 352-358.
200. Pei JJ, Braak H, Gong CX, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF (2002) Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer's disease neurofibrillary degeneration. Acta Neuropathol (Berl) 104, 369-376.
201. Johnson GV, Hartigan JA (1999) Tau protein in normal and Alzheimer's disease brain: An update. J Alzheimers Dis 1, 329-351.
202. Godemann R, Biernat J, Mandelkow E, Mandelkow EM (1999) Phosphorylation of tau protein by recombinant GSK-3beta: Pronounced phosphorylation at select Ser/Thr-Pro motifs but no phosphorylation at Ser262 in the repeat domain. FEBS Lett 454, 157-164.
203. Liu F, Liang Z, Wegiel J, Hwang YW, Iqbal K, Grundke-Iqbal I, Ramakrishna N, GongCX(2008) Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J 22, 3224-3233.
204. Buee-Scherrer V, Goedert M (2002) Phosphorylation of microtubule- associated protein tau by stress-activated protein kinases in intact cells. FEBS Lett 515, 151-154.
205. Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A (2005) Evidence that phosphorylation of the microtubuleassociated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci 118, 397-408.
206. Rahman A, Grundke-Iqbal I, Iqbal K (2005) Phosphothreonine-212 of Alzheimer abnormally hyperphosphorylated tau is a preferred substrate of protein phosphatase-1. Neurochem Res 30, 277-287.
207. Bennecib M, Gong CX, Grundke-Iqbal I, Iqbal K (2000) 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 Lett 485, 87-93.
208. Merrick SE, Demoise DC, Lee VM (1996) Site-specific dephosphorylation of tau protein at Ser202/Thr205 in response to microtubule depolymerization in cultured human neurons involves protein phosphatase 2A. J Biol Chem 271, 5589-5594.
209. Liu F, Zaidi T, Iqbal K, Grundke-Iqbal I, Gong CX (2002) Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5. Neuroscience 115, 829-837.
210. Wei Q, Holzer M, Brueckner MK, Liu Y, Arendt T (2002) Dephosphorylation of tau protein by calcineurin triturated into neural living cells. Cell Mol Neurobiol 22, 13-24.
211. Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1994) Alzheimer's disease abnormally phosphorylated tau is dephosphorylated by protein phosphatase-2B (calcineurin). J Neurochem 62, 803-806.
212. Rahman A, Grundke-Iqbal I, Iqbal K (2006) PP2B isolated from human brain preferentially dephosphorylates Ser-262 and Ser-396 of the Alzheimer disease abnormally hyperphosphorylated tau. J Neural Transm 113, 219-230.
213. Gong CX, Liu F, Wu G, Rossie S, Wegiel J, Li L, Grundke-Iqbal I, Iqbal K (2004) Dephosphorylation of microtubule-associated protein tau by protein phosphatase 5. J Neurochem 88, 298-310.
214. Liu F, Iqbal K, Grundke-Iqbal I, Rossie S, Gong CX (2005) Dephosphorylation of tau by protein phosphatase 5: Impairment in Alzheimer's disease. J Biol Chem 280, 1790-1796.