Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease

Gen He, Wenjie Luo, Peng Li, Christine Remmers, William J. Netzer, Joseph Hendrick, Karima Bettayeb, Marc Flajolet, Fred Gorelick, Lawrence P. Wennogle and Paul Greengard ()
Additional contact information
Gen He: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Wenjie Luo: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Peng Li: Intra-Cellular Therapies, Inc., Audubon Biomedical Science and Technology Park, 3960 Broadway, New York, New York 10032, USA
Christine Remmers: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
William J. Netzer: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Joseph Hendrick: Intra-Cellular Therapies, Inc., Audubon Biomedical Science and Technology Park, 3960 Broadway, New York, New York 10032, USA
Karima Bettayeb: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Marc Flajolet: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Fred Gorelick: Yale University School of Medicine
Lawrence P. Wennogle: Intra-Cellular Therapies, Inc., Audubon Biomedical Science and Technology Park, 3960 Broadway, New York, New York 10032, USA
Paul Greengard: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA

Nature, 2010, vol. 467, issue 7311, 95-98

Abstract: New Alzheimer's target Much of the work on potential anti-Alzheimer's disease drugs has been focused on compounds that reduce the accumulation of neurotoxic amyloid-β peptide in the brain. This has met with little success, in part because agents that block γ-secretase also block processing of Notch, a signalling protein essential for many homeostatic functions, resulting in severe side effects. Now the discovery of a γ-secretase activating protein (GSAP) that selectively controls amyloid-β generation without influencing Notch cleavage suggests a possible new target for anti-Alzheimer's drugs. The anticancer drug imatinib (Gleevec), known to inhibit amyloid-β formation without affecting Notch cleavage, is shown to act via an effect on GSAP. This suggests that GSAP inhibitors that can cross the blood–brain barrier (unlike imatinib) may hold promise for treating Alzheimer's disease.

Date: 2010
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DOI: 10.1038/nature09325

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