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

Christopher J. Phiel, Christina A. Wilson, Virginia M.-Y. Lee and Peter S. Klein ()
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Christopher J. Phiel: Department of Medicine, Division of Hematology–Oncology and Howard Hughes Medical Institute
Christina A. Wilson: University of Pennsylvania School of Medicine
Virginia M.-Y. Lee: University of Pennsylvania School of Medicine
Peter S. Klein: Department of Medicine, Division of Hematology–Oncology and Howard Hughes Medical Institute

Nature, 2003, vol. 423, issue 6938, 435-439

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01640

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