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Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Background

There is evidence of increased systemic expression of active GSK3B in Alzheimer’s disease patients, which apparently is associated with the formation of senile plaques and neurofibrillary tangles. Due to its central role in the pathogenesis of AD, GSK3B is currently a promising target of the pharmaceutical industry. Whilst trials with specific GSK inhibitors in AD are under way, major attention has been focused on the neuroprotective effects of lithium. Whereas the direct and indirect inhibitory effects of lithium over GSK3 activity have been documented by several groups, its effects over Gsk3 transcription have not yet been addressed.

Methods

We used quantitative PCR to evaluate the transcriptional regulation of Gsk3a and Gsk3b in lithium-treated primary cultures of rat cortical and hippocampal neurons.

Results

We found a significant and dose-dependent reduction in the expression of Gsk3b, which was specific to hippocampal cells. This same effect was further confirmed in vivo by measuring Gsk3 expression in different brain regions and in peripheral leukocytes of adult rats treated with lithium.

Conclusion

Our studies show that LiCl can modulate Gsk3b transcription in vitro and in vivo. This observation suggest new regulatory effects of lithium over Gsk3b, contributing to the better understanding of its mechanisms of action, offering a new and complementary explanation for Gsk3b modulation and reinforcing its potential for the inhibition of key pathological pathways in Alzheimer’s disease.

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References

  1. Aplin AE, Gibb GM, Jacobsen JS, Gallo JM, Anderton BH (1996) In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta. J Neurochem 67:699–707

    PubMed  CAS  Google Scholar 

  2. Bhat RV, Budd Haeberlein SL, Avila J (2004) Glycogen synthase kinase 3: a drug target for CNS therapies. J Neurochem 89:1313–1317

    Article  PubMed  CAS  Google Scholar 

  3. Cade JF (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust 2:349–352

    PubMed  CAS  Google Scholar 

  4. Chalecka-Franaszek E, Chuang DM (1999) Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA 96:8745–8750

    Article  PubMed  CAS  Google Scholar 

  5. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  6. De Sarno P, Li X, Jope RS (2002) Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology 43:1158–1164

    Article  PubMed  Google Scholar 

  7. De Strooper B, Woodgett J (2003) Alzheimer’s disease: mental plaque removal. Nature 423:392–393

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Gould TD, Quiroz JA, Singh J, Zarate CA, Manji HK (2004) Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers. Mol Psychiatry 9:734–755

    Article  PubMed  CAS  Google Scholar 

  10. Guan RJ, Khatra BS, Cohlberg JA (1991) Phosphorylation of bovine neurofilament proteins by protein kinase FA (glycogen synthase kinase 3). J Biol Chem 266:8262–8267

    PubMed  CAS  Google Scholar 

  11. Hernández F, Borrell J, Guaza C, Avila J, Lucas JJ (2002) Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments. J Neurochem 83:1529–1533

    Article  PubMed  Google Scholar 

  12. Hooper C, Markevich V, Plattner F, Killick R, Schofield E, Engel T et al (2007) Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci 25:81–86

    Article  PubMed  Google Scholar 

  13. Hoshi M, Sato M, Kondo S, Takashima A, Noguchi K, Takahashi M et al (1995) Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. J Biochem (Tokyo) 118:683–685

    CAS  Google Scholar 

  14. Hye A, Kerr F, Archer N, Foy C, Poppe M, Brown R et al (2005) Glycogen synthase kinase-3 is increased in white cells early in Alzheimer’s disease. Neurosci Lett 373:1–4

    Article  PubMed  CAS  Google Scholar 

  15. Jope RS (2003) Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 24:441–443

    Article  PubMed  CAS  Google Scholar 

  16. Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93:8455–8459

    Article  PubMed  CAS  Google Scholar 

  17. Lau KF, Miller CC, Anderton BH, Shaw PC (1999) Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter. Genomics 60:121–128

    Article  PubMed  CAS  Google Scholar 

  18. Lee KF, Chan JY, Lau KF, Lee WC, Miller CC, Anderton BH et al (2000) Molecular cloning and expression analysis of human glycogen synthase kinase-3 alpha promoter. Brain Res Mol Brain Res 84:150–157

    Article  PubMed  CAS  Google Scholar 

  19. Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP, Squire A et al (2004) GSK-3 beta inhibition reverses axonal transport defects and behavioral phenotypes in Drosophila. Mol Psychiatry 9:522–530

    Article  PubMed  CAS  Google Scholar 

  20. Mussmann R, Geese M, Harder F, Kegel S, Andag U, Lomow A, Burk U et al (2007) Inhibition of glycogen synthase kinase (GSK) 3 promotes replication and survival of pancreatic beta cells. J Biol Chem 282:12030–12037

    Article  PubMed  CAS  Google Scholar 

  21. Nunes PV, Forlenza OV, Gattaz WF (2007) Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 190:359–360

    Article  PubMed  Google Scholar 

  22. Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423:435–439

    Article  PubMed  CAS  Google Scholar 

  23. Stambolic V, Ruel L, Woodgett JR (1997) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 7:196

    Google Scholar 

  24. Stambolic V, Woodgett JR (1994) Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J 303:701–704

    PubMed  CAS  Google Scholar 

  25. Sun X, Sato S, Murayama O, Murayama M, Park JM, Yamaguchi H et al (2002) Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci Lett 321:61–64

    Article  PubMed  CAS  Google Scholar 

  26. Takahashi M, Tomizawa K, Kato R, Sato K, Uchida T et al (1994) Localization and developmental changes of tau protein kinase I/glycogen synthase kinase-3 beta in rat brain. J Neurochem 63:245–255

    Article  PubMed  CAS  Google Scholar 

  27. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034

    Article  PubMed  Google Scholar 

  28. Zhang F, Phiel CJ, Spece L, Gurvich N, Klein PSJ (2003) Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. Biol Chem 278:33067–33077

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The research presented here was supported by ABADHS (Associação Beneficente Alzira Denise Herzog da Silva), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and FAPESP (Fundação do Amparo à Pesquisa do Estado de São Paulo). The authors recognize the valuable technical support of Sergio Catanozi, Jussara Cordeiro Rocha and Vanessa de Jesus de Paula, and the kind help of Prof. Suely Kazue Nagahashi Marie with the organization of space for our studies in her animal house.

Conflict of interest The authors declare no conflict of interest

Author information

Author notes

  1. Emmanuel Dias-Neto

    Present address: MD Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Unit 1374, Houston, TX, 77030, USA

Authors and Affiliations

  1. Laboratory of Neurosciences – LIM27, Department & Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil

    Camila Teixeira Mendes, Fábio Borges Mury, Orestes Vicente Forlenza, Emmanuel Dias-Neto & Wagner Farid Gattaz

  2. Institute of Biomedical Sciences – Department of Biotechnology, University of Sao Paulo, Sao Paulo, Brazil

    Camila Teixeira Mendes & Fábio Borges Mury

  3. Fleury Institute, Molecular Methods Sector, Sao Paulo, Brazil

    Eloísa de Sá Moreira & Fernando Lopes Alberto

  4. Rua Dr. Ovidio Pires de Campos, 785, São Paulo, SP, 05403-010, Brazil

    Emmanuel Dias-Neto & Wagner Farid Gattaz

Authors
  1. Camila Teixeira Mendes
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  2. Fábio Borges Mury
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Corresponding authors

Correspondence to Emmanuel Dias-Neto or Wagner Farid Gattaz.

Additional information

E. Dias-Neto and W.F. Gattaz contributed equally to this work.

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Mendes, C.T., Mury, F.B., de Sá Moreira, E. et al. Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease. Eur Arch Psychiatry Clin Neurosci 259, 16–22 (2009). https://doi.org/10.1007/s00406-008-0828-5

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  • DOI: https://doi.org/10.1007/s00406-008-0828-5

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