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GSK-3α regulates production of Alzheimer's disease amyloid-β peptides

Nature volume 423, pages 435–439 (2003)Cite this article

Abstract

Alzheimer's disease is associated with increased production and aggregation of amyloid-β (Aβ) peptides1. Aβ peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE2, followed by presenilin-dependent γ-secretase cleavage3. Presenilin interacts with nicastrin4,5, APH-1 and PEN-2 (ref. 6), all of which are required for γ-secretase function. Presenilins also interact with α-catenin, β-catenin7,8 and glycogen synthase kinase-3β (GSK-3β)9,10,11, but a functional role for these proteins in γ-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor12, block the production of Aβ peptides by interfering with APP cleavage at the γ-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Aβ peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3α, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3α offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.

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Figure 1: Lithium reduces secreted Aβ40 and Aβ42, and causes accumulation of APP C-terminal fragments.
Figure 2: GSK-3 inhibitors reduce Aβ independently of β-catenin stabilization.
Figure 3: GSK-3α is required for Aβ production.
Figure 4: Lithium blocks Aβ accumulation in cultured neurons and in the brains of mice overproducing Aβ peptides.

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References

  1. Selkoe, D. J. Presenilin, Notch, and the genesis and treatment of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 11039–11041 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Vassar, R. et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999)

    Article  CAS  Google Scholar 

  3. De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998)

    Article  ADS  CAS  Google Scholar 

  4. Esler, W. P. et al. Activity-dependent isolation of the presenilin–γ-secretase complex reveals nicastrin and a γ secretase substrate. Proc. Natl Acad. Sci. USA 99, 2720–2725 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Edbauer, D., Winkler, E., Haass, C. & Steiner, H. Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation. Proc. Natl Acad. Sci. USA 99, 8666–8671 (2002)

    Article  ADS  CAS  Google Scholar 

  6. Francis, R. et al. aph-1 and pen-2 are required for Notch pathway signalling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev. Cell 3, 85–97 (2002)

    Article  CAS  Google Scholar 

  7. Soriano, S. et al. Presenilin 1 negatively regulates β-catenin/T cell factor/lymphoid enhancer factor-1 signalling independently of β-amyloid precursor protein and notch processing. J. Cell Biol. 152, 785–794 (2001)

    Article  CAS  Google Scholar 

  8. Yu, G. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54 (2000)

    Article  ADS  CAS  Google Scholar 

  9. Takashima, A. et al. Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau. Proc. Natl Acad. Sci. USA 95, 9637–9641 (1998)

    Article  ADS  CAS  Google Scholar 

  10. Kang, D. E. et al. Presenilin 1 facilitates the constitutive turnover of β-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the β-catenin-signalling pathway. J. Neurosci. 19, 4229–4237 (1999)

    Article  CAS  Google Scholar 

  11. Kang, D. E. et al. Presenilin couples the paired phosphorylation of β-catenin independent of axin: implications for β-catenin activation in tumorigenesis. Cell 110, 751–762 (2002)

    Article  CAS  Google Scholar 

  12. Phiel, C. J. & Klein, P. S. Molecular targets of lithium action. Annu. Rev. Pharmacol. Toxicol. 41, 789–813 (2001)

    Article  CAS  Google Scholar 

  13. Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455–8459 (1996)

    Article  ADS  CAS  Google Scholar 

  14. Sun, X. et al. Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci. Lett. 321, 61–64 (2002)

    Article  CAS  Google Scholar 

  15. De Strooper, B. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999)

    Article  ADS  CAS  Google Scholar 

  16. Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517 (1999)

    Article  ADS  CAS  Google Scholar 

  17. Schroeter, E. H., Kisslinger, J. A. & Kopan, R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386 (1998)

    Article  ADS  CAS  Google Scholar 

  18. Bain, J., McLaughlan, H., Elliott, M. & Cohen, P. The specificities of protein kinase inhibitors—an update. Biochem. J. 371, 199–204 (2003)

    Article  CAS  Google Scholar 

  19. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001)

    Article  ADS  CAS  Google Scholar 

  20. Hoeflich, K. P. et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406, 86–90 (2000)

    Article  ADS  CAS  Google Scholar 

  21. Siman, R. et al. Presenilin-1 P264L knock-in mutation: differential effects on Aβ production, amyloid deposition, and neuronal vulnerability. J. Neurosci. 20, 8717–8726 (2000)

    Article  CAS  Google Scholar 

  22. Kirschenbaum, F., Hsu, S. C., Cordell, B. & McCarthy, J. V. Substitution of a glycogen synthase kinase-3β phosphorylation site in presenilin 1 separates presenilin function from β-catenin signaling. J. Biol. Chem. 276, 7366–7375 (2001)

    Article  CAS  Google Scholar 

  23. Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414, 212–216 (2001)

    Article  ADS  CAS  Google Scholar 

  24. Alvarez, G. et al. Regulation of tau phosphorylation and protection against β-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer's disease. Bipolar Disord. 4, 153–165 (2002)

    Article  CAS  Google Scholar 

  25. Forman, M. S., Cook, D. G., Leight, S., Doms, R. W. & Lee, V. M.-Y. Differential effects of the Swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells. J. Biol. Chem. 272, 32247–32253 (1997)

    Article  CAS  Google Scholar 

  26. Pleasure, S. J., Page, C. & Lee, V. M.-Y. Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons. J. Neurosci. 12, 1802–1815 (1992)

    Article  CAS  Google Scholar 

  27. Suzuki, N. et al. An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants. Science 264, 1336–1340 (1994)

    Article  ADS  CAS  Google Scholar 

  28. Turner, R. S., Suzuki, N., Chyung, A. S., Younkin, S. G. & Lee, V. M.-Y. Amyloids β40 and β42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J. Biol. Chem. 271, 8966–8970 (1996)

    Article  CAS  Google Scholar 

  29. Cook, D. G. et al. Alzheimer's Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nature Med. 3, 1021–1023 (1997)

    Article  CAS  Google Scholar 

  30. Wilson, C. A., Doms, R. W., Zheng, H. & Lee, V. M.-Y. Presenilins are not required for Aβ42 production in the early secretory pathway. Nature Neurosci. 5, 849–855 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank R. Doms for critical reading of the manuscript, and T. Kadesch, J. Yang, G. Wertheim, K. Phiel and members of the Klein, Lee and Doms laboratories for helpful discussions. We are grateful to J. Woodgett, R. Kopan, B. Gumbiner, K. Kinzler and B. Vogelstein for plasmids, S. Sisodia for CHO-APP695 cells, and D. Flood for PS1P264L knock-in mice. Monoclonal antibodies for the Aβ sandwich ELISA were provided by N. Suzuki and Tekeda Pharmaceuticals. C.A.W. was a Howard Hughes Predoctoral Fellow. This work was supported by grants from the National Institute on Aging (to V.M.-Y.L.) and the National Institute of Mental Health (to P.S.K.).

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  1. Christopher J. Phiel, Christina A. Wilson and Virginia M.-Y. Lee: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Division of Hematology–Oncology and Howard Hughes Medical Institute,

    Christopher J. Phiel & Peter S. Klein

  2. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 415 Curie Blvd, Philadelphia, Philadelphia, 19104-6148, USA

    Christina A. Wilson & Virginia M.-Y. Lee

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Correspondence to Peter S. Klein.

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Phiel, C., Wilson, C., Lee, VY. et al. GSK-3α regulates production of Alzheimer's disease amyloid-β peptides. Nature 423, 435–439 (2003). https://doi.org/10.1038/nature01640

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