Journal Mobile Options
Table of Contents
Vol. 11, No. 5, 2002
Issue release date: September–October 2002
Neurosignals 2002;11:251–261
(DOI:10.1159/000067423)

GSK3β Signalling: Casting a Wide Net in Alzheimer’s Disease

Bhat R.V. · Budd S.L.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

Glycogen synthase kinase-3β (GSK3β) is a kinase that plays a pivotal role in numerous cellular functions from modulation of microtubule dynamics and cell death. It also affects higher functions such as cognition and mood. Deregulation of GSK3β activity in the adult brain is implicated in several CNS disorders, such as affective disorders, schizophrenia, stroke and neurodegenerative diseases, such as Alzheimer’s disease (AD). In AD, GSK3β has a major role in microtubule stability by its ability to phosphorylate the microtubule associated protein tau. The present review focuses on recent developments in the understanding of GSK3β with an emphasis on events likely to be critical to the pathophysiology of AD.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Woodgett JR: Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 1990;9:2431–2438.
  2. Woodgett JR: cDNA cloning and properties of glycogen synthase kinase-3. Methods Enzymol 1991;200:564–577.
  3. Rylatt DB, Embi N, Cohen P: Glycogen synthase kinase-2 from rabbit skeletal muscle is activated by the calcium-dependent regulator protein. FEBS Lett 1979;98:76–80.
  4. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR: Glycogen synthase kinase-3:Functions in oncogenesis and development. Biochim Biophys Acta 1992;1114:147–162.
  5. Leroy K, Brion JP: Developmental expression and localization of glycogen synthase kinase-3beta in rat brain. J Chem Neuroanat 1999;16:279–293.
  6. Mukai F, Ishiguro K, Sano Y, Fujita SC: Alternate splicing isoform of tau protein kinase I/glycogen synthase kinase 3β. J Neurochem 2002;81:1073–1083.
  7. Wang QM, Park IK, Fiol CJ, Roach PJ, DePaoli-Roach AA: Isoform differences in substrate recognition by glycogen synthase kinases 3 alpha and 3 beta in the phosphorylation of phosphatase inhibitor 2. Biochemistry 1994;33:143–147.
  8. Frame S, Cohen P, Biondi RM: A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell 2001;7:1321–1327.
  9. Lin C, Yiming L, Semenov M, Han C, Baeg G-H, Tan Y, Zhang Z, Lin X, He X: Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002;108:837–847.
  10. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785–789.
  11. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S: Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 1998;95:11211–11216.
  12. Armstrong JL, Bonavaud SM, Toole BJ, Yeaman SJ: Regulation of glycogen synthesis by amino acids in cultured human muscle cells. J Biol Chem 2001;276:952–956.
  13. Cui H, Meng Y, Bulleit RF: Inhibition of glycogen synthase kinase 3beta activity regulates proliferation of cultured cerebellar granule cells. Brain Res Dev Brain Res 1998;111:177–188.

    External Resources

  14. Quevedo C, Alcazar A, Salinas M: Two different signal transduction pathways are implicated in the regulation of initiation factor 2B activity in insulin-like growth factor-1-stimulated neuronal cells. J Biol Chem 2000;275:19192–19197.
  15. Pap M, Cooper GM: Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 1998;273:19929–19932.
  16. Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR: Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 1993;12:803–808.
  17. Kim L, Liu J, Kimmel AR: The novel tyrosine kinase ZAK1 activates GSK3 to direct cell fate specification. Cell 1999;99:399–408.
  18. Lesort M, Jope RS, Johnson GV: Insulin transiently increases tau phosphorylation: Involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase. J Neurochem 1999;72:576–584.
  19. Haritgan Xiong WC, Johnson GV: Glycogen synthase kinase 3β is tyrosine phosphorylated by Pyk2. Biochem Biophys Res Commun 2001;284:485–489.
  20. Hartigan JA, Johnson GV: Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway. J Biol Chem 1999;274:21395–21401.
  21. Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW, Lee CM: Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci USA 2000;97:11074–11079.
  22. Frame S, Cohen P: GSK3 takes centre stage more than 20 years after its discovery. Biochem J 2001;359:1–16.
  23. Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH: Crystal structure of glycogen synthase kinase 3 beta: Structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 2001;105:721–732.
  24. Bax B, Carter PS, Lewis C, Guy AR, Bridges A, Tanner R, Pettman G, Mannix C, Culbert AA, Brown MJ, Smith DG, Reith AD: The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation. Structure (Camb) 2001;9:1143–1152.
  25. Blair LA, Bence-Hanulec KK, Mehta S, Franke T, Kaplan D, Marshall J: Akt-dependent potentiation of L channels by insulin-like growth factor-1 is required for neuronal survival. J Neurosci 1999;19:1940–1951.
  26. Takashima A, Noguchi K, Michel G, Mercken M, Hoshi M, Ishiguro K, Imahori K: Exposure of rat hippocampal neurons to amyloid beta peptide (25–35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci Lett 1996;203:33–36.
  27. Bhat RV, Leonov S, Luthman J, Scott CW, Lee C: Interactions between GSK3 and caspase signalling pathways during NGF deprivation-induced cell death. Alzheimers Dis, in press.
  28. Sanchez C, Diaz-Nido J, Avila J: Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Prog Neurobiol 2000;61:133–168.
  29. Yu JS, Yang SD: Protein kinase FA/glycogen synthase kinase-3 predominantly phosphorylates the in vivo site Thr97-Pro in brain myelin basic protein: Evidence for Thr-Pro and Ser-Arg-X-X-Ser as consensus sequence motifs. J Neurochem 1994;62:1596–1603.
  30. Mackie K, Sorkin BC, Nairn AC, Greengard P, Edelman GM, Cunningham BA: Identification of two protein kinases that phosphorylate the neural cell-adhesion molecule, N-CAM. J Neurosci 1989;9:1883–1896.
  31. Guan RJ, Khatra BS, Cohlberg JA: Phosphorylation of bovine neurofilament proteins by protein kinase FA (glycogen synthase kinase 3). J Biol Chem 1991;266:8262–8267.
  32. Guidato S, Tsai LH, Woodgett J, Miller CC: Differential cellular phosphorylation of neurofilament heavy side-arms by glycogen synthase kinase-3 and cyclin-dependent kinase-5. J Neurochem 1996;66:1698–1706.
  33. Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC: Human dynamin-like protein interacts with the glycogen synthase kinase 3beta. Biochem Biophys Res Commun 1998;249:697–703.
  34. Chen CH, Hwang SL, Howng SL, Chou CK, Hong YR: Three rat brain alternative splicing dynamin-like protein variants: Interaction with the glycogen synthase kinase 3beta and action as a substrate. Biochem Biophys Res Commun 2000;268:893–898.
  35. Hong YR, Chen CH, Chang JH, Wang S, Sy WD, Chou CK, Howng SL: Cloning and characterization of a novel human ninein protein that interacts with the glycogen synthase kinase 3beta. Biochim Biophys Acta 2000;1492:513–516.
  36. Struthers RS, Vale WW, Arias C, Sawchenko PE, Montminy MR: Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant. Nature 1991;350:622–624.
  37. Davis GW, Schuster CM, Goodman CS: Genetic dissection of structural and functional components of synaptic plasticity. III. CREB is necessary for presynaptic functional plasticity. Neuron 1996;17:669–679.
  38. Mermelstein PG, Bito H, Deisseroth K, Tsien RW: Critical dependence of cAMP response element-binding protein phosphorylation on L-type calcium channels supports a selective response to EPSPs in preference to action potentials. J Neurosci 2000;20:266–273.
  39. Pham TA, Rubenstein JL, Silva AJ, Storm DR, Stryker MP: The CRE/CREB pathway is transiently expressed in thalamic circuit development and contributes to refinement of retinogeniculate axons. Neuron 2001;31:409–420.
  40. Bevilaqua LR, Cammarota M, Paratcha G, de Stein ML, Izquierdo I, Medina JH: Experience-dependent increase in cAMP-responsive element binding protein in synaptic and nonsynaptic mitochondria of the rat hippocampus. Eur J Neurosci 1999;11:3753–3756.
  41. Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD: Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 1999;286:2358–2361.
  42. Montminy MR, Bilezikjian LM: Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 1987;328:175–178.
  43. Waeber G, Habener JF: Nuclear translocation and DNA recognition signals colocalized within the bZIP domain of cyclic adenosine 3′,5′-monophosphate response element-binding protein CREB. Mol Endocrinol 1991;5:1431–1438.
  44. Gonzalez GA, Yamamoto KK, Fischer WH, Karr D, Menzel P, Biggs W 3rd, Vale WW, Montminy MR: A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence. Nature 1989;337:749–752.
  45. Gonzalez GA, Montminy MR: Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 1989;59:675–680.
  46. Fiol CJ, Williams JS, Chou CH, Wang QM, Roach PJ, Andrisani OM: A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. J Biol Chem 1994;269:32187–32193.
  47. Bullock BP, Habener JF: Phosphorylation of the cAMP response element binding protein CREB by cAMP-dependent protein kinase A and glycogen synthase kinase-3 alters DNA-binding affinity, conformation, and increases net charge. Biochemistry 1998;37:3795–3809.
  48. Grimes CA, Jope RS: CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium. J Neurochem 2001;78:1219–1232.
  49. Jain J, McCaffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, Curran T, Rao A: The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 1993;365:352–355.
  50. Ruff VA, Leach KL: Direct demonstration of NFATp dephosphorylation and nuclear localization in activated HT-2 cells using a specific NFATp polyclonal antibody. J Biol Chem 1995;270:22602–22607.
  51. Loh C, Shaw KT, Carew J, Viola JP, Luo C, Perrino BA, Rao A: Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity. J Biol Chem 1996;271:10884–10891.
  52. Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR: Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 1997;275:1930–1934.
  53. Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR: L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 1999;401:703–708.
  54. Grimes CA, Jope RS: The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 2001;65:391–426.
  55. Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere CA, Imahori K: Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol (Berl) 1996;92:232–241.
  56. Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF: Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol 1999;58:1010–1019.
  57. Leroy K, Boutajangout A, Authelet M, Woodgett JR, Anderton BH, Brion JP: The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer’s disease. Acta Neuropathol (Berl) 2002;103:91–99.
  58. Aplin AE, Gibb GM, Jacobsen JS, Gallo JM, Anderton BH: In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta. J Neurochem 1996;67:699–707.
  59. Takashima A, Yamaguchi H, Noguchi K, Michel G, Ishiguro K, Sato K, Hoshino T, Hoshi M, Imahori K: Amyloid beta peptide induces cytoplasmic accumulation of amyloid protein precursor via tau protein kinase I/glycogen synthase kinase-3 beta in rat hippocampal neurons. Neurosci Lett 1995;198:83–86.
  60. Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M, Ishiguro K, Yamaguchi H: Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res 1998;31:317–323.
  61. Tomidokoro Y, Ishiguro K, Harigaya Y, Matsubara E, Ikeda M, Park JM, Yasutake K, Kawarabayashi T, Okamoto K, Shoji M: Abeta amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice. Neurosci Lett 2001;299:169–172.
  62. Hoshi M, Takashima A, Murayama M, Yasutake K, Yoshida N, Ishiguro K, Hoshino T, Imahori K: Nontoxic amyloid beta peptide 1–42 suppresses acetylcholine synthesis. Possible role in cholinergic dysfunction in Alzheimer’s disease. J Biol Chem 1997;272:2038–2041.
  63. Hoshi M, Takashima A, Noguchi K, Murayama M, Sato M, Kondo S, Saitoh Y, Ishiguro K, Hoshino T, Imahori K: Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci USA 1996;93:2719–2723.
  64. Schmidt ML, Zhukareva V, Newell KL, Lee VM, Trojanowski JQ: Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol (Berl) 2001;101:518–524.
  65. Yoshiyama Y, Lee VM, Trojanowski JQ: Frontotemporal dementia and tauopathy. Curr Neurol Neurosci Rep 2001;1:413–421.
  66. Lau L, Schachter JB, Seymour PA, Sanner MA: Tau protein phosphorylation as a therapeutic target in Alzheimer’s disease. Curr Top Med Chem 2002;2:395–415.
  67. Mattson MP: Neuronal death and GSK-3beta: A tau fetish? Trends Neurosci 2001;24:255–256.
  68. Xie H, Litersky JM, Hartigan JA, Jope RS, Johnson GV: The interrelationship between selective tau phosphorylation and microtubule association. Brain Res 1998;798:173–183.
  69. Mandelkow EM, Drewes G, Biernat J, Gustke N, Van Lint J, Vandenheede JR, Mandelkow E: Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett 1992;314:315–321.
  70. Mandelkow EM, Mandelkow E: Tau in Alzheimer’s disease. Trends Cell Biol 1998;8:425–427.
  71. Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S, Uchida T, Imahori K: Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 1993;325:167–172.
  72. Lovestone S, Reynolds CH, Latimer D, Davis DR, Anderton BH, Gallo JM, Hanger D, Mulot S, Marquardt B, Stabel S, et al: Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol 1994;4:1077–1086.
  73. Sang H, Lu Z, Li Y, Ru B, Wang W, Chen J: Phosphorylation of tau by glycogen synthase kinase 3beta in intact mammalian cells influences the stability of microtubules. Neurosci Lett 2001;312:141–144.
  74. Hanger DP, Betts JC, Loviny TL, Blackstock WP, Anderton BH: New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer’s disease brain using nanoelectrospray mass spectrometry. J Neurochem 1998;71:2465–2476.
  75. Klein PS, Melton DA: A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996;93:8455–8459.
  76. Hong M, Chen DC, Klein PS, Lee VM: Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 1997;272:25326–25332.
  77. Lucas FR, Goold RG, Gordon-Weeks PR, Salinas PC: Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium. J Cell Sci 1998;111:1351–1361.
  78. Berling B, Wille H, Roll B, Mandelkow EM, Garner C, Mandelkow E: Phosphorylation of microtubule-associated proteins MAP2a, b and MAP2c at Ser136 by proline-directed kinases in vivo and in vitro. Eur J Cell Biol 1994;64:120–130.
  79. Sanchez C, Tompa P, Szucs K, Friedrich P, Avila J: Phosphorylation and dephosphorylation in the proline-rich C-terminal domain of microtubule-associated protein 2. Eur J Biochem 1996;241:765–771.
  80. Sanchez C, Perez M, Avila J: GSK3beta-mediated phosphorylation of the microtubule-associated protein 2C (MAP2C) prevents microtubule bundling. Eur J Cell Biol 2000;79:252–260.
  81. Lovestone S, Davis DR, Webster MT, Kaech S, Brion JP, Matus A, Anderton BH: Lithium reduces tau phosphorylation: Effects in living cells and in neurons at therapeutic concentrations. Biol Psychiatry 1999;45:995–1003.
  82. Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST: Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 2002;21:281–293.
  83. Sengupta A, Wu Q, Grundke-Iqbal I, Iqbal K, Singh TJ: Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5. Mol Cell Biochem 1997;167:99–105.
  84. Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, Van Lint J, Vandenheede J, Moechars D, Loos R, Van Leuven F: Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem 2000;275:41340–41349.
  85. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J: Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 2001;20:27–39.
  86. Jackson GR, Wiedau-Pazos M, Sang T, Wagle N, Brown CA, Massachi S, Geschwind DH: Human Wild-Type Tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 2002;34:509–519.
  87. Guo Q, Sopher BL, Furukawa K, Pham DG, Robinson N, Martin GM, Mattson MP: Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: Involvement of calcium and oxyradicals. J Neurosci 1997;17:4212–4222.
  88. Vestling M, Wiehager B, Tanii H, Cowburn RF: Akt activity in presenilin 1 wild-type and mutation transfected human SH-SY5Y neuroblastoma cells after serum deprivation and high glucose stress. J Neurosci Res 2001;66:448–456.
  89. Bursztajn S, DeSouza R, McPhie DL, Berman SA, Shioi J, Robakis NK, Neve RL: Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis. J Neurosci 1998;18:9790–9799.
  90. Takashima A, Murayama M, Murayama O, Kohno T, Honda T, Yasutake K, Nihonmatsu N, Mercken M, Yamaguchi H, Sugihara S, Wolozin B: Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc Natl Acad Sci USA 1998;95:9637–9641.
  91. Gantier R, Gilbert D, Dumanchin C, Campion D, Davoust D, Toma F, Frebourg T: The pathogenic L392V mutation of presenilin 1 decreases the affinity to glycogen synthase kinase-3 beta. Neurosci Lett 2000;283:217–220.
  92. Zhou J, Liyanage U, Medina M, Ho C, Simmons AD, Lovett M, Kosik KS: Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Neuroreport 1997;8:2085–2090.
  93. Kang DE, Soriano S, Frosch MP, Collins T, Naruse S, Sisodia SS, Leibowitz G, Levine F, Koo EH: Presenilin 1 facilitates the constitutive turnover of beta-catenin: Differential activity of Alzheimer’s disease-linked PS1 mutants in the beta-catenin-signaling pathway. J Neurosci 1999;19:4229–4237.
  94. Xia W, Ray WJ, Ostaszewski BL, Rahmati T, Kimberly WT, Wolfe MS, Zhang J, Goate AM, Selkoe DJ: Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta-protein generation. Proc Natl Acad Sci USA 2000;97:9299–9304.
  95. Elyaman W, Terro F, Wong NS, Hugon J: In vivo activation and nuclear translocation of phosphorylated glycogen synthase kinase-3beta in neuronal apoptosis: Links to tau phosphorylation. Eur J Neurosci 2002;15:651–660.
  96. Weihl CC, Ghadge GD, Kennedy SG, Hay N, Miller RJ, Roos RP: Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB. J Neurosci 1999;19:5360–5369.
  97. Killick R, Pollard CC, Asuni AA, Mudher AK, Richardson JC, Rupniak HT, Sheppard PW, Varndell IM, Brion JP, Levey AI, Levy OA, Vestling M, Cowburn R, Lovestone S, Anderton BH: Presenilin 1 independently regulates beta-catenin stability and transcriptional activity. J Biol Chem 2001;276:48554–48561.
  98. Cook D, Fry MJ, Hughes K, Sumathipala R, Woodgett JR, Dale TC: Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C. EMBO J 1996;15:4526–4536.
  99. Wodarz A, Nusse R: Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998;14:59–88.
  100. Patapoutian A, Reichardt LF: Roles of Wnt proteins in neural development and maintenance. Curr Opin Neurobiol 2000;10:392–399.
  101. Smalley MJ, Sara E, Paterson H, Naylor S, Cook D, Jayatilake H, Fryer LG, Hutchinson L, Fry MJ, Dale TC: Interaction of axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. EMBO J 1999;18:2823–2835.
  102. Li L, Yuan H, Weaver CD, Mao J, Farr GH 3rd, Sussman DJ, Jonkers J, Kimelman D, Wu D: Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J 1999;18:4233–4240.
  103. Thomas GM, Frame S, Goedert M, Nathke I, Polakis P, Cohen P: A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin. FEBS Lett 1999;458:247–251.
  104. Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P: Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol 1998;8:573–581.
  105. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W: Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996;382:638–642.
  106. Berezovska O, Xia MQ, Hyman BT: Notch is expressed in adult brain, is coexpressed with presenilin-1, and is altered in Alzheimer disease. J Neuropathol Exp Neurol 1998;57:738–745.
  107. Cotter D, Honavar M, Lovestone S, Raymond L, Kerwin R, Anderton B, Everall I: Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex. Acta Neuropathol (Berl) 1999;98:465–472.
  108. Cross DA, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD: Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem 2001;77:94–102.
  109. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC: Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 2000;7:793–803.
  110. Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L: Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 2001;276:251–260.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50