Abstract
Accumulation of neurotoxic amyloid-β is a major hallmark of Alzheimer’s disease1. Formation of amyloid-β is catalysed by γ-secretase, a protease with numerous substrates2,3. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective γ-secretase inhibitors that can reduce amyloid-β formation without impairing cleavage of other γ-secretase substrates, especially Notch, which is essential for normal biological functions3,4. Here we report the discovery of a novel γ-secretase activating protein (GSAP) that drastically and selectively increases amyloid-β production through a mechanism involving its interactions with both γ-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-β production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-β concentrations. Knockdown of GSAP in a mouse model of Alzheimer’s disease reduces levels of amyloid-β and plaque development. GSAP represents a type of γ-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-β formation without affecting Notch cleavage5, achieves its amyloid-β-lowering effect by preventing GSAP interaction with the γ-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-β-lowering therapeutic target without affecting other key functions of γ-secretase.
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Acknowledgements
We thank E. Woo and B. Chait for their help with protein identification. We thank Y. M. Li for providing us with the biotinylated transition-state analogue. We thank B. Turner and S. Ku for their technical support. This work was supported by NIH grant AG09464 to P.G., DOD grant W81XWH-09-1-0402 to P.G., the Fisher Center for Alzheimer’s Research Foundation and the F. M. Kirby Foundation.
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G.H., W.L., P.L., C.R., J.H. and K.B. performed experiments; W.J.N. was involved in experimental design; M.F. performed sequence analysis; G.H., W.L., L.P.W. and P.G. designed the study; G.H., W.L., F.G., L.P.W. and P.G. wrote the paper; all authors discussed the results and commented on the manuscript.
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L.P.W., P.L. and J.H. were full-time employees of Intra-Cellular Therapies, Inc. during these studies. A patent application based on this study has been filed.
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He, G., Luo, W., Li, P. et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature 467, 95–98 (2010). https://doi.org/10.1038/nature09325
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DOI: https://doi.org/10.1038/nature09325
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