Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  ADS  CAS  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 

Download references


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.

Author information

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.

Corresponding author

Correspondence to Paul Greengard.

Ethics declarations

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.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and Supplementary Figures 1-11 with legends. (PDF 1087 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing