Skip to main content
SpringerLink
Log in

Overexpression of GSK3βS9A Resulted in Tau Hyperphosphorylation and Morphology Reminiscent of Pretangle-Like Neurons in the Brain of PDGSK3β Transgenic Mice

  • Published:
Transgenic Research Aims and scope Submit manuscript

Abstract

It has been demonstrated that GSK3β is involved in Alzheimer Disease (AD) pathogenesis. In order to understand the underlying mechanism, we have generated and characterized transgenic mice in which the constitutively active human GSK3β(with S9A mutation) was overexpressed in the brain under the control of the platelet-derived growth factor (PDGF) B-chain promoter. Varying levels of human GSK3βS9A transgene protein expression was observed in six of the seven founders generated. Line 3083, 3107, 3112 and 3125 displayed higher GSK3βS9A protein expression levels. Immunostaining analysis demonstrated that transgene expression was observed mainly in cortex and hippocampus of transgenic brain. Expression of human GSK3β transgene did not significantly change the brain total GSK3β protein levels in any of the generated mouse lines, as comparing to age matched wild type mice. Although significant kinase activity was detected in human GSK3βS9A transgene protein extracted from brains of all six expressing lines, significant increase in total GSK3βS9A kinase activity was observed only in the offspring of line 3083 and 3107. By analyzing the offspring from several transgenic mouse lines, including lines other than 3083 and 3107, it was found that overexpressed constitutively active human GSK3βS9A resulted in hyperphosphorylation of tau and morphology reminiscent of pretangle-like neurons in cortex and hippocampus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ahmed NN, Franke TF, Bellacosa A, Datta K, Gonzalez-Portal ME and Taguchi T et al. (1993) The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 8: 1957–1963.

    PubMed  Google Scholar 

  • Ali A, Hoeflich KP and Woodgett JR (2001) Glycogen synthase kinase-3: properties, functions, and regulation. Chem Rev 101: 2527–2540.

    Article  PubMed  Google Scholar 

  • Andra K, Abramowski D, Duke M, Probst A, Wiederhold KH and Burki K et al. (1996) Expression of APP in transgenic mice: a comparison of neuron-specific promoters. Neurobiol Aging 17: 183–190.

    Article  PubMed  Google Scholar 

  • Baum L, Hansen L, Masliah E and Saitoh T (1996) Glycogen synthase kinase 3 alteration in Alzheimer disease is related to neurofibrillary tangle formation. Mol Chem Neuropathol 29: 253–261.

    PubMed  Google Scholar 

  • Bhat RV and Budd SL (2002) GSK3beta signalling: casting a wide net in Alzheimer’s disease. Neurosignals 11: 251–261.

    Article  PubMed  Google Scholar 

  • Brinster RL, Allen JM, Behringer RR, Gelinas RE and Palmiter RD (1988) Introns increase transcriptional efficiency in transgenic mice. Proc Natl Acad Sci USA 85: 836–840.

    PubMed  Google Scholar 

  • Brownlees J, Irving NG, Brion JP, Gibb BJ, Wagner U and Woodgett J et al. (1997) Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3beta transgenes. Neuroreport 8: 3251–3255.

    PubMed  Google Scholar 

  • Cross DA, Alessi DR, Cohen P, Andjelkovich M and Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785–789.

    Article  PubMed  Google Scholar 

  • Cross DA, Culbert AA, Chalmers KA, Facci L, Skaper SD and Reith AD (2001) Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem 77: 94–102.

    PubMed  Google Scholar 

  • Ferreira A, Lu Q, Orecchio L and Kosik KS (1997) Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar A beta. Mol Cell Neurosci 9: 220–234.

    Article  PubMed  Google Scholar 

  • Frame S and Cohen P (2001) GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359: 1–16.

    Article  PubMed  Google Scholar 

  • Games D, Adams D, Alessandrini R, Barbour R, Berthelette P and Blackwell C et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373: 523–527.

    Article  PubMed  Google Scholar 

  • Georgopoulos S, McKee A, Kan HY and Zannis VI (2002) Generation and characterization of two transgenic mouse lines expressing human ApoE2 in neurons and glial cells. Biochemistry 41: 9293–9301.

    Article  PubMed  Google Scholar 

  • Gotz J, Chen F, Barmettler R and Nitsch RM (2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276: 529–534.

    Article  PubMed  Google Scholar 

  • Hetman M, Cavanaugh JE, Kimelman D and Xia Z (2000) Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20: 2567–2574.

    PubMed  Google Scholar 

  • Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O and Woodgett JR (2000) Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406: 86–90.

    Article  PubMed  Google Scholar 

  • Hong M, Chen DC, Klein PS and Lee VM (1997) Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 272: 25326–25332.

    Article  PubMed  Google Scholar 

  • Hoshi M, Sato M, Matsumoto S, Noguchi A, Yasutake K and Yoshida N et al (2003) Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta. Proc Natl Acad Sci USA 100: 6370–6375. Epub 2003 May 6315.

  • Imahori K and Uchida T (1997) Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. J Biochem (Tokyo) 121: 179–188.

    Google Scholar 

  • Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M and Kobayashi S et al. (1993) Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 325: 167–172.

    Article  PubMed  Google Scholar 

  • Kaytor MD and Orr HT (2002) The GSK3 beta signaling cascade and neurodegenerative disease. Curr Opin Neurobiol 12: 275–278.

    Article  PubMed  Google Scholar 

  • Lee KY, Clark AW, Rosales JL, Chapman K, Fung T and Johnston RN (1999) Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain. Neurosci Res 34: 21–29.

    Article  PubMed  Google Scholar 

  • Li B, Greenberg N, Stephens LC, Meyn R, Medina D and Rosen JM (1994) Preferential overexpression of a 172Arg-&gt Leu mutant p53 in the mammary gland of transgenic mice results in altered lobuloalveolar development. Cell Growth Differ 5: 711–721.

    PubMed  Google Scholar 

  • Li B, Murphy KL, Laucirica R, Kittrell F, Medina D and Rosen JM (1998) A transgenic mouse model for mammary carcinogenesis. Oncogene 16: 997–1007.

    Article  PubMed  Google Scholar 

  • Lovestone S, Reynolds CH, Latimer D, Davis DR, Anderton BH and Gallo JM et al. (1994) Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol 4: 1077–1086.

    Article  PubMed  Google Scholar 

  • Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R and Avila J (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20: 27–39.

    Article  PubMed  Google Scholar 

  • Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V and Naidu A et al. (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274: 6483–6492.

    Article  PubMed  Google Scholar 

  • Munoz-Montano JR, Moreno FJ, Avila J and Diaz-Nido J (1997) Lithium inhibits Alzheimer’s disease-like tau protein phosphorylation in neurons. FEBS Lett 411: 183–188.

    Article  PubMed  Google Scholar 

  • Pap M and Cooper GM (1998) Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 273: 19929–19932.

    Article  PubMed  Google Scholar 

  • Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K and Winblad B et al. (1999) Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol 58: 1010–1019.

    PubMed  Google Scholar 

  • Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW and Lang I et al. (2002) Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 68: 568–578.

    Article  PubMed  Google Scholar 

  • Russ C, Lovestone S and Powell JF (2001) Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer’s disease. Mol Psychiatry 6: 320–324.

    Article  PubMed  Google Scholar 

  • Saito Y, Vandenheede JR and Cohen P (1994) The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cells. Biochem J 303: 27–31.

    PubMed  Google Scholar 

  • Sasahara M, Fries JW, Raines EW, Gown AM, Westrum LE and Frosch Mp et al. (1991) PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model. Cell 64: 217–227.

    Article  PubMed  Google Scholar 

  • Spittaels K, Van den Haute C, Van Dorpe J, Terwel D, Vandezande K and Lasrado R et al. (2002) Neonatal neuronal overexpression of glycogen synthase kinase-3 beta reduces brain size in transgenic mice. Neuroscience 113: 797–808.

    Article  PubMed  Google Scholar 

  • Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C and Rothacher S et al. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94: 13287–13292.

    Article  PubMed  Google Scholar 

  • Sun A, Liu M, Nguyen XV and Bing G (2003) P38 MAP kinase is activated at early stages in Alzheimer’s disease brain. Exp Neurol 183: 394–405.

    Article  PubMed  Google Scholar 

  • Sutherland C, Leighton IA and Cohen P (1993) Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J 296: 15–19.

    PubMed  Google Scholar 

  • Takashima A, Noguchi K, Michel G, Mercken M, Hoshi M and Ishiguro K et al. (1996) 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 203: 33–36.

    Article  PubMed  Google Scholar 

  • Takashima A, Honda T, Yasutake K, Michel G, Murayama O and Murayama M et al. (1998) 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 31: 317–323.

    Article  PubMed  Google Scholar 

  • Van Dorpe J, Smeijers L, Dewachter I, Nuyens D, Spittaels K and Van Den Haute C et al. (2000) Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons. Am J Pathol 157: 1283–1298.

    PubMed  Google Scholar 

  • Wang QM, Roach PJ and Fiol CJ (1994) Use of a synthetic peptide as a selective substrate for glycogen synthase kinase 3. Anal Biochem 220: 397–402.

    Article  PubMed  Google Scholar 

  • Woodgett JR (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9: 2431–2438.

    PubMed  Google Scholar 

  • Woodgett JR (1991) cDNA cloning and properties of glycogen synthase kinase-3. Methods Enzymol 200: 564–577.

    PubMed  Google Scholar 

  • Zhu X, Sun Z, Lee HG, Siedlak SL, Perry G and Smith MA (2003) Distribution, levels, and activation of MEK1 in Alzheimer’s disease. J Neurochem 86: 136–142.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lilly Research Laboratories, Eli Lilly and company, Lilly corporate center, Drop code 0510, Indianapolis, Indiana, 46285, USA

    Baolin Li, John Ryder, Yuan Su, Steven A Moore Jr, Feng Liu, Patricia Solenberg, Kellie Brune, Niles Fox, Binhui Ni & Yan Zhou

  2. Department of Pediatrics University of Louisville School of Medicine, Kosair Children's Hospital Research Institute, Louisville, KY, 40202

    Rugao Liu

Authors
  1. Baolin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Ryder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuan Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven A Moore Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Feng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patricia Solenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kellie Brune
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Niles Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Binhui Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rugao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baolin Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, B., Ryder, J., Su, Y. et al. Overexpression of GSK3βS9A Resulted in Tau Hyperphosphorylation and Morphology Reminiscent of Pretangle-Like Neurons in the Brain of PDGSK3β Transgenic Mice. Transgenic Res 13, 385–396 (2004). https://doi.org/10.1023/B:TRAG.0000040039.44899.6f

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:TRAG.0000040039.44899.6f

Search

Navigation