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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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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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