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


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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Figure 1: Identification of GSAP as an imatinib target.
Figure 2: GSAP regulates amyloid-β production but does not influence Notch cleavage.
Figure 3: GSAP interacts with γ-secretase and APP-CTF but not with Notch.
Figure 4: Knockdown of GSAP reduces amyloid-β production and plaque development in a mouse model of Alzheimer’s disease.


  1. Selkoe, D. J. Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001)

    CAS  Article  Google Scholar 

  2. Steiner, H., Fluhrer, R. & Haass, C. Intramembrane proteolysis by gamma-secretase. J. Biol. Chem. 283, 29627–29631 (2008)

    CAS  Article  Google Scholar 

  3. Lathia, J. D., Mattson, M. P. & Cheng, A. Notch: from neural development to neurological disorders. J. Neurochem. 107, 1471–1481 (2008)

    CAS  Article  Google Scholar 

  4. Wong, G. T. et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 279, 12876–12882 (2004)

    CAS  Article  Google Scholar 

  5. Netzer, W. J. et al. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc. Natl Acad. Sci. USA 100, 12444–12449 (2003)

    ADS  CAS  Article  Google Scholar 

  6. Placanica, L. et al. Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes. J. Biol. Chem. 284, 2967–2977 (2009)

    CAS  Article  Google Scholar 

  7. Dougan, D. A., Mogk, A., Zeth, K., Turgay, K. & Bukau, B. AAA+ proteins and substrate recognition, it all depends on their partner in crime. FEBS Lett. 529, 6–10 (2002)

    CAS  Article  Google Scholar 

  8. Visintin, R., Prinz, S. & Amon, A. CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis. Science 278, 460–463 (1997)

    ADS  CAS  Article  Google Scholar 

  9. Lefranc-Jullien, S., Sunyach, C. & Checler, F. APPε, the ε-secretase-derived N-terminal product of the β-amyloid precursor protein, behaves as a type I protein and undergoes α-, β-, and γ-secretase cleavages. J. Neurochem. 97, 807–817 (2006)

    CAS  Article  Google Scholar 

  10. Jankowsky, J. L. et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 17, 157–165 (2001)

    CAS  Article  Google Scholar 

  11. van Es, J. H. et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005)

    ADS  CAS  Article  Google Scholar 

  12. Milano, J. et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol. Sci. 82, 341–358 (2004)

    CAS  Article  Google Scholar 

  13. Beel, A. J. & Sanders, C. R. Substrate specificity of gamma-secretase and other intramembrane proteases. Cell. Mol. Life Sci. 65, 1311–1334 (2008)

    CAS  Article  Google Scholar 

  14. Chen, F. et al. TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 440, 1208–1212 (2006)

    ADS  CAS  Article  Google Scholar 

  15. Thathiah, A. et al. The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science 323, 946–951 (2009)

    ADS  CAS  Article  Google Scholar 

  16. Serneels, L. et al. γ-secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer’s disease. Science 324, 639–642 (2009)

    ADS  CAS  Article  Google Scholar 

  17. Takami, M. et al. γ-secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J. Neurosci. 29, 13042–13052 (2009)

    CAS  Article  Google Scholar 

  18. Kume, H. & Kametani, F. Abeta 11–40/42 production without gamma-secretase epsilon-site cleavage. Biochem. Biophys. Res. Commun. 349, 1356–1360 (2006)

    CAS  Article  Google Scholar 

  19. Wiley, J. C., Hudson, M., Kanning, K. C., Schecterson, L. C. & Bothwell, M. Familial Alzheimer’s disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. J. Neurochem. 94, 1189–1201 (2005)

    CAS  Article  Google Scholar 

  20. Bentahir, M. et al. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J. Neurochem. 96, 732–742 (2006)

    CAS  Article  Google Scholar 

  21. Green, R. C. et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. J. Am. Med. Assoc. 302, 2557–2564 (2009)

    CAS  Article  Google Scholar 

  22. Dai, H., Marbach, P., Lemaire, M., Hayes, M. & Elmquist, W. F. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J. Pharmacol. Exp. Ther. 304, 1085–1092 (2003)

    CAS  Article  Google Scholar 

  23. Wang, H. et al. Presenilins and gamma-secretase inhibitors affect intracellular trafficking and cell surface localization of the gamma-secretase complex components. J. Biol. Chem. 279, 40560–40566 (2004)

    CAS  Article  Google Scholar 

  24. Xu, H. et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nature Med. 4, 447–451 (1998)

    CAS  Article  Google Scholar 

  25. Li, Y. M. et al. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc. Natl Acad. Sci. USA 97, 6138–6143 (2000)

    ADS  CAS  Article  Google Scholar 

  26. Seibler, J. et al. Reversible gene knockdown in mice using a tight, inducible shRNA expression system. Nucleic Acids Res. 35, e54 (2007)

    Article  Google Scholar 

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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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Authors and Affiliations



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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Correspondence to Paul Greengard.

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Competing interests

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).

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