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The secretases: enzymes with therapeutic potential in Alzheimer disease

Nature Reviews Neurology volume 6, pages 99–107 (2010)Cite this article

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Abstract

The amyloid hypothesis has yielded a series of well-validated candidate drug targets with potential for the treatment of Alzheimer disease (AD). Three proteases that are involved in the processing of amyloid precursor protein—α-secretase, β-secretase and γ-secretase—are of particular interest as they are central to the generation and modulation of amyloid-β peptide and can be targeted by small compounds in vitro and in vivo. Given that these proteases also fulfill other important biological roles, inhibiting their activity will clearly be inherently associated with mechanism-based toxicity. Carefully determining a suitable therapeutic window and optimizing the selectivity of the drug treatments towards amyloid precursor protein processing might be ways of overcoming this potential complication. Secretase inhibitors are likely to be the first small-molecule therapies aimed at AD modification that will be fully tested in the clinic. Success or failure of these first-generation AD therapies will have enormous consequences for further drug development efforts for AD and possibly other neurodegenerative conditions.

Key Points

  • α-Secretase, β-secretase and γ-secretase are proteases that control the production of amyloid-β (Aβ) in the brain

  • The secretases represent the most promising drug targets for Alzheimer disease therapies

  • The α-secretase activity is mediated by a series of membrane-bound proteases, further research is needed to identify which of these proteases are most important for processing amyloid precursor protein

  • β-Secretase and γ-secretase research has progressed enormously and compounds designed to attenuate their activity are in clinic trials

  • The current trials test only whether elimination or attenuating Aβ in moderate to advanced AD could be beneficial

  • A real test of the amyloid hypothesis will require drug testing at earlier stages of the disease

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Figure 1: Processing of APP by the secretases.
Figure 2: Structures of the secretases.

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References

  1. Knopman, D. S. Mediterranean diet and late-life cognitive impairment: a taste of benefit. JAMA 302, 686–687 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lazarov, O. et al. Environmental enrichment reduces Aβ levels and amyloid deposition in transgenic mice. Cell 120, 701–713 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Reinhard, C., Hebert, S. S. & De Strooper, B. The amyloid-β precursor protein: integrating structure with biological function. EMBO J. 24, 3996–4006 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sisodia, S. S., Koo, E. H., Beyreuther, K., Unterbeck, A. & Price, D. L. Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing. Science 248, 492–495 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Weidemann, A. et al. Proteolytic processing of the Alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases. J. Biol. Chem. 274, 5823–5829 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Seubert, P. et al. Secretion of β-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 361, 260–263 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Golde, T. E., Estus, S., Younkin, L. H., Selkoe, D. J. & Younkin, S. G. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255, 728–730 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Haass, C., Koo, E. H., Mellon, A., Hung, A. Y. & Selkoe, D. J. Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357, 500–503 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. De Strooper, B. et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Haass, C. & Selkoe, D. J. Cellular processing of β-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75, 1039–1042 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Hung, A. Y. et al. Activation of protein kinase C inhibits cellular production of the amyloid β-protein. J. Biol. Chem. 268, 22959–22962 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Skovronsky, D. M., Moore, D. B., Milla, M. E., Doms, R. W. & Lee, V. M. Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-golgi network. J. Biol. Chem. 275, 2568–2575 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Rossner, S. et al. Constitutive overactivation of protein kinase C in guinea pig brain increases α-secretory APP processing without decreasing β-amyloid generation. Eur. J. Neurosci. 12, 3191–3200 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Gowing, E. et al. Chemical characterization of Aβ 17–42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. J. Biol. Chem. 269, 10987–10990 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Higgins, L. S., Murphy, G. M. Jr, Forno, L. S., Catalano, R. & Cordell, B. P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain. Am. J. Pathol. 149, 585–596 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ring, S. et al. The secreted β-amyloid precursor protein ectodomain APPsα is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J. Neurosci. 27, 7817–7826 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lammich, S. et al. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922–3927 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Postina, R. et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113, 1456–1464 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Asai, M. et al. Putative function of ADAM9, ADAM10, and ADAM17 as APP α-secretase. Biochem. Biophys. Res. Commun. 301, 231–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Buxbaum, J. D. et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765–27767 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Koike, H. et al. Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein. Biochem. J. 343, 371–375 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tanabe, C. et al. ADAM19 is tightly associated with constitutive Alzheimer's disease APP α-secretase in A172 cells. Biochem. Biophys. Res. Commun. 352, 111–117 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Farzan, M., Schnitzler, C. E., Vasilieva, N., Leung, D. & Choe, H. BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein. Proc. Natl Acad. Sci. USA 97, 9712–9717 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yan, R., Munzner, J. B., Shuck, M. E. & Bienkowski, M. J. BACE2 functions as an alternative α-secretase in cells. J. Biol. Chem. 276, 34019–34027 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Weskamp, G. et al. Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. Mol. Cell. Biol. 22, 1537–1544 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hartmann, D. et al. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for α-secretase activity in fibroblasts. Hum. Mol. Genet. 11, 2615–2624 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Maretzky, T. et al. ADAM10 mediates E-cadherin shedding and regulates epithelial cell–cell adhesion, migration, and β-catenin translocation. Proc. Natl Acad. Sci. USA 102, 9182–9187 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Reiss, K. et al. ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and β-catenin nuclear signalling. EMBO J. 24, 742–752 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Allinson, T. M., Parkin, E. T., Turner, A. J. & Hooper, N. M. ADAMs family members as amyloid precursor protein α-secretases. J. Neurosci. Res. 74, 342–352 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Bandyopadhyay, S., Goldstein, L. E., Lahiri, D. K. & Rogers, J. T. Role of the APP non-amyloidogenic signaling pathway and targeting α-secretase as an alternative drug target for treatment of Alzheimer's disease. Curr. Med. Chem. 14, 2848–2864 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Tippmann, F., Hundt, J., Schneider, A., Endres, K. & Fahrenholz, F. Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 6, 1643–1654 (2009).

    Article  CAS  Google Scholar 

  34. Caccamo, A. et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49, 671–682 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Wolf, B. A. et al. Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid β-protein production in human neuronal NT2N cells. J. Biol. Chem. 270, 4916–4922 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Zimmermann, M. et al. Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines. J. Neurochem. 90, 1489–1499 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci. 14, 419–427 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Vassar, R. et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533–537 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Lin, X. et al. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc. Natl Acad. Sci. USA 97, 1456–1460 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cole, S. L. & Vassar, R. The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. J. Biol. Chem. 283, 29621–29625 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Luo, Y. et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci. 4, 231–232 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Cai, H. et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat. Neurosci. 4, 233–234 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Roberds, S. L. et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet. 10, 1317–1324 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Dominguez, D. et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J. Biol. Chem. 280, 30797–30806 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Ohno, M. et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41, 27–33 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Laird, F. M. et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693–11709 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. McConlogue, L. et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J. Biol. Chem. 282, 26326–26334 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Nishitomi, K. et al. BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J. Neurochem. 99, 1555–1563 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Singer, O. et al. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat. Neurosci. 8, 1343–1349 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Yan, R., Han, P., Miao, H., Greengard, P. & Xu, H. The transmembrane domain of the Alzheimer's β-secretase (BACE1) determines its late Golgi localization and access to β-amyloid precursor protein (APP) substrate. J. Biol. Chem. 276, 36788–36796 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Kitazume, S. et al. Alzheimer's β-secretase, β-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc. Natl Acad. Sci. USA 98, 13554–13559 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lichtenthaler, S. F. et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J. Biol. Chem. 278, 48713–48719 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Li, Q. & Sudhof, T. C. Cleavage of amyloid-β precursor protein and amyloid-β precursor-like protein by BACE 1. J. Biol. Chem. 279, 10542–10550 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Pastorino, L. et al. BACE (β-secretase) modulates the processing of APLP2 in vivo. Mol. Cell. Neurosci. 25, 642–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Eggert, S. et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α-, β-, γ-, and ε-like cleavages: modulation of APLP-1 processing by n-glycosylation. J. Biol. Chem. 279, 18146–18156 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. von Arnim, C. A. et al. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J. Biol. Chem. 280, 17777–17785 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Wong, H. K. et al. β Subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J. Biol. Chem. 280, 23009–23017 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Kim, D.Y. et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat. Cell Biol. 9, 755–764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hu, X. et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J. 22, 2970–2980 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Willem, M. et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664–666 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Hu, X et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 9, 1520–1525 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Silvestri, R. Boom in the development of non-peptidic β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease. Med. Res. Rev. 29, 295–338 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Hills, I. D. & Vacca, J. P. Progress toward a practical BACE-1 inhibitor. Curr. Opin. Drug Discov. Devel. 10, 383–391 (2007).

    CAS  PubMed  Google Scholar 

  66. Rajendran, L. et al. Efficient inhibition of the Alzheimer's disease β-secretase by membrane targeting. Science 320, 520–523 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. De Strooper, B. Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex. Neuron 38, 9–12 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Wolfe, M. S. & Kopan, R. Intramembrane proteolysis: theme and variations. Science 305, 1119–1123 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Takasugi, N. et al. The role of presenilin cofactors in the γ-secretase complex. Nature 422, 438–441 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Edbauer, D. et al. Reconstitution of γ-secretase activity. Nat. Cell Biol. 5, 486–488 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Shah, S. et al. Nicastrin functions as a γ-secretase-substrate receptor. Cell 122, 435–447 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Chavez-Gutierrez, L. et al. Glu(332) in the nicastrin ectodomain is essential for γ-secretase complex maturation but not for its activity. J. Biol. Chem. 283, 20096–20105 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Hébert, S. S. et al. Coordinated and widespread expression of γ-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol. Dis. 17, 260–272 (2004).

    Article  PubMed  CAS  Google Scholar 

  74. Shirotani, K., Edbauer, D., Prokop, S., Haass, C. & Steiner, H. Identification of distinct γ-secretase complexes with different APH-1 variants. J. Biol. Chem. 279, 41340–41345 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Ma, G., Li, T., Price, D. L. & Wong, P. C. APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development. J. Neurosci. 25, 192–198 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Serneels, L. et al. Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc. Natl Acad. Sci. USA 102, 1719–1724 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Osenkowski, P. et al. Cryoelectron microscopy structure of purified γ-secretase at 12 A resolution. J. Mol. Biol. 385, 642–652 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Lazarov, V. K. et al. Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores. Proc. Natl Acad. Sci. USA 103, 6889–6894 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tolia, A., Chavez-Gutierrez, L. & De Strooper, B. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the γ-secretase complex. J. Biol. Chem. 281, 27633–27642 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Sato, C., Morohashi, Y., Tomita, T. & Iwatsubo, T. Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. J. Neurosci. 26, 12081–12088 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kopan, R. & Ilagan, M. X. γ-Secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, 499–504 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Kakuda, N. et al. Equimolar production of amyloid β-protein and amyloid precursor protein intracellular domain from β-carboxyl-terminal fragment by γ-secretase. J. Biol. Chem. 281, 14776–14786 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Golde, T. E., Eckman, C. B. & Younkin, S. G. Biochemical detection of Aβ isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochim. Biophys. Acta 1502, 172–187 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Jarrett, J. T., Berger, E. P. & Lansbury, P. T. Jr. The carboxy terminus of β amyloid protein is critical for the seeding of amyloid formation: Implications for pathogenesis of Alzheimer's disease. Biochemistry 32, 4693–4697 (1993).

    Article  CAS  PubMed  Google Scholar 

  87. McGowan, E. et al. Aβ42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191–199 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang, R., Wang, B., He, W. & Zheng, H. Wild-type presenilin 1 protects against Alzheimer's disease mutation-induced amyloid pathology. J. Biol. Chem. 281, 15330–15336 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Kim, J. et al. Aβ40 inhibits amyloid deposition in vivo. J. Neurosci. 27, 627–633 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wolfe, M. S. Inhibition and modulation of γ-secretase for Alzheimer's disease. Neurotherapeutics 5, 391–398 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bateman, R. J. et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 66, 48–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Siemers, E. R. et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin. Neuropharmacol. 30, 317–325 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Dovey, H. F. et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem. 76, 173–181 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Abramowski, D. et al. Dynamics of Aβ turnover and deposition in different β-amyloid precursor protein transgenic mouse models following γ-secretase inhibition. J. Pharmacol. Exp. Ther. 327, 411–424 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. De Strooper, B. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Wong, P. C. et al. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387, 288–292 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Shen, J. et al. Skeletal and CNS defects in presenilin-1-deficient mice. Cell 89, 629–639 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Searfoss, G. H. et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J. Biol. Chem. 278, 46107–46116 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  100. Li, T. et al. Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of γ-secretase. J. Biol. Chem. 282, 32264–32273 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Yankner, B. A. et al. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245, 417–420 (1989).

    Article  CAS  PubMed  Google Scholar 

  102. Siemers, E. R. et al. Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66, 602–604 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Fraering, P. C. et al. γ-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J. Biol. Chem. 280, 41987–41996 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fagan, T. DC: New γ-secretase inhibitors hit APP, spare Notch. The AlzGene Database. Alzheimer Research Forum [online], (2008).

  106. Mayer, S. C. et al. Discovery of begacestat, a Notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer's disease. J. Med. Chem. 51, 7348–7351 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414, 212–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Kukar, T. & Golde, T. E. Possible mechanisms of action of NSAIDs and related compounds that modulate γ-secretase cleavage. Curr. Top. Med. Chem. 8, 47–53 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kukar, T. et al. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nat. Med. 11, 545–550 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Weggen, S. et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β42 production by direct modulation of γ-secretase activity. J. Biol. Chem. 278, 31831–31837 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. 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. JAMA 302, 2557–2564 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kukar, T. L. et al. Substrate-targeting γ-secretase modulators. Nature 453, 925–929 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pissarnitski, D. Advances in gamma-secretase modulation. Curr. Opin. Drug Discov. Devel. 10, 392–402 (2007).

    CAS  PubMed  Google Scholar 

  114. Klunk, W. E. & Mathis, C. A. The future of amyloid-beta imaging: a tale of radionuclides and tracer proliferation. Curr. Opin. Neurol. 21, 683–687 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a NIH/NIA grant (number AG25531) to T. Golde. B. De Strooper was supported by an Artificial SynApse (IWT-ASAP) grant, the Federal Office for Scientific Affairs, Belgium (IUAP P6/43), a Methusalem grant from the Flemish Government and a grant from the European Union (MEMOSAD, F2-2007-200611). R. Vassar received support from the NIH (grant numbers: P01 AG021184, R01 AG022560 and R01 AG030142), the Alzheimer's Association and the MetLife Foundation.

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  1. Center for Human Genetics, VIB and KULeuven, Herestraat 49, Box 602, 3000, Leuven, Belgium

    Bart De Strooper

  2. Department of Cell and Molecular Biology, Northwestern University, Chicago, 60611, IL, USA

    Robert Vassar

  3. Department of Neuroscience, Mayo Clinic College of Medicine, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, 32224, FL, USA

    Todd Golde

Authors
  1. Bart De Strooper
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  2. Robert Vassar
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  3. Todd Golde
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Corresponding author

Correspondence to Bart De Strooper.

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Competing interests

B. De Strooper has received honoraria from Eisai, Eli Lilly, EnVivo, Johnson & Johnson and Probiodrug for consulting and has received research funding from Eli Lilly, EnVivo and Johnson & Johnson. He also holds the following European patent (EP) applications (EP 00200671.6, EP 01201015.3, EP 01202228.1, EP 02078915.2, EP 04106516.0, EP 05107454.0, EP 06120346.9, EP 07106482.8, EP 08063269, EP 09053985) with the Flanders institute for Biotechnology. T. Golde holds one patent application (WO0178721) with the Mayo Clinic. R. Vasser declares no competing interests.

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De Strooper, B., Vassar, R. & Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6, 99–107 (2010). https://doi.org/10.1038/nrneurol.2009.218

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