γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all γ-secretases causes serious toxicity. Evolving insights suggest that selective inhibition of one of these proteases, or more subtle modulation of γ-secretases by stimulating their carboxypeptidase-like activity but sparing their endopeptidase activity, are potentially highly interesting approaches. The rapidly growing knowledge of regulation, assembly, and specificity of these intriguing protein complexes and the potential advent of high-resolution structural information could dramatically change the perspective on safe and efficacious γ-secretase inhibition in various disorders.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Karran E, Mercken M, De Strooper B. 1.  2011. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10:698–712 [Google Scholar]
  2. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A. 2.  et al. 2012. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367:795–804 [Google Scholar]
  3. Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J. 3.  et al. 2013. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12:957–65 [Google Scholar]
  4. De Strooper B. 4.  2010. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol. Rev. 90:465–94 [Google Scholar]
  5. Karran E, Hardy J. 5.  2014. Antiamyloid therapy for Alzheimer's disease—are we on the right road?. N. Engl. J. Med. 370:377–78 [Google Scholar]
  6. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B. 6.  et al. 2014. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370:311–21 [Google Scholar]
  7. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W. 7.  et al. 2014. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370:322–33 [Google Scholar]
  8. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B. 8.  et al. 2013. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369:341–50 [Google Scholar]
  9. Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U. 9.  et al. 2012. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 31:3157–68 [Google Scholar]
  10. Zhou L, Barão S, Laga M, Bockstael K, Borgers M. 10.  et al. 2012. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J. Biol. Chem. 287:25927–40 [Google Scholar]
  11. Rochin L, Hurbain I, Serneels L, Fort C, Watt B. 11.  et al. 2013. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc. Natl. Acad. Sci. USA 110:10658–63 [Google Scholar]
  12. Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A. 12.  et al. 2013. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 32:2015–28 [Google Scholar]
  13. Jurisch-Yaksi N, Sannerud R, Annaert W. 13.  2013. A fast growing spectrum of biological functions of γ-secretase in development and disease. Biochim. Biophys. Acta 1828:2815–27 [Google Scholar]
  14. Clark RF, Hutton M, Fuldner M, Froelich S, Karran E. 14.  et al. 1995. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat. Genet. 11:219–22 [Google Scholar]
  15. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J. 15.  et al. 1995. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973–77 [Google Scholar]
  16. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M. 16.  et al. 1995. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376:775–78 [Google Scholar]
  17. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G. 17.  et al. 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375:754–60 [Google Scholar]
  18. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G. 18.  et al. 1998. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–90 [Google Scholar]
  19. De Strooper B. 19.  2003. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active γ-secretase complex. Neuron 38:9–12 [Google Scholar]
  20. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. 20.  1999. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398:513–17 [Google Scholar]
  21. Hayashi I, Urano Y, Fukuda R, Isoo N, Kodama T. 21.  et al. 2004. Selective reconstitution and recovery of functional γ-secretase complex on budded baculovirus particles. J. Biol. Chem. 279:38040–46 [Google Scholar]
  22. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. 22.  2003. Reconstitution of γ-secretase activity. Nat. Cell Biol. 5:486–88 [Google Scholar]
  23. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. 23.  2003. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2. Proc. Natl. Acad. Sci. USA 100:6382–87 [Google Scholar]
  24. Osenkowski P, Li H, Ye W, Li D, Aeschbach L. 24.  et al. 2009. Cryoelectron microscopy structure of purified γ-secretase at 12 Å resolution. J. Mol. Biol. 385:642–52 [Google Scholar]
  25. Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y. 25.  et al. 2007. Active γ-secretase complexes contain only one of each component. J. Biol. Chem. 282:33985–93 [Google Scholar]
  26. Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ III. 26.  2013. Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J. Neurosci. 33:11606–17 [Google Scholar]
  27. Schroeter EH, Ilagan MXG, Brunkan AL, Hecimovic S, Li YM. 27.  et al. 2003. A presenilin dimer at the core of the γ-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc. Natl. Acad. Sci. USA 100:13075–80 [Google Scholar]
  28. Erez E, Fass D, Bibi E. 28.  2009. How intramembrane proteases bury hydrolytic reactions in the membrane. Nature 459:371–78 [Google Scholar]
  29. Tolia A, Chávez-Gutiérrez L, De Strooper B. 29.  2006. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the γ-secretase complex. J. Biol. Chem. 281:27633–42 [Google Scholar]
  30. Sato C, Morohashi Y, Tomita T, Iwatsubo T. 30.  2006. Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. J. Neurosci. 26:12081–88 [Google Scholar]
  31. Tolia A, Horré K, De Strooper B. 31.  2008. Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of γ-secretase. J. Biol. Chem. 283:19793–803 [Google Scholar]
  32. Sato C, Takagi S, Tomita T, Iwatsubo T. 32.  2008. The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the γ-secretase. J. Neurosci. 28:6264–71 [Google Scholar]
  33. Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo T. 33.  2010. Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase. J. Neurosci. 30:15943–50 [Google Scholar]
  34. Li X, Dang S, Yan C, Gong X, Wang J, Shi Y. 34.  2013. Structure of a presenilin family intramembrane aspartate protease. Nature 493:56–61 [Google Scholar]
  35. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M. 35.  et al. 2009. γ-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of β-carboxyl terminal fragment. J. Neurosci. 29:13042–52 [Google Scholar]
  36. Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H. 36.  et al. 2003. Potential link between amyloid β-protein 42 and C-terminal fragment γ 49–99 of β-amyloid precursor protein. J. Biol. Chem. 278:24294–301 [Google Scholar]
  37. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N. 37.  et al. 2005. Longer forms of amyloid β protein: implications for the mechanism of intramembrane cleavage by γ-secretase. J. Neurosci. 25:436–45 [Google Scholar]
  38. Kakuda N, Funamoto S, Yagishita S, Takami M, Osawa S. 38.  et al. 2006. Equimolar production of amyloid β-protein and amyloid precursor protein intracellular domain from β-carboxyl-terminal fragment by β-secretase. J. Biol. Chem. 281:14776–86 [Google Scholar]
  39. Yagishita S, Morishima-Kawashima M, Ishiura S, Ihara Y. 39.  2008. Aβ46 is processed to Aβ40 and Aβ43, but not to Aβ42, in the low density membrane domains. J. Biol. Chem. 283:733–38 [Google Scholar]
  40. Matsumura N, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H. 40.  et al. 2014. γ-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of β-carboxyl terminal fragment. J. Biol. Chem. 289:5109–21 [Google Scholar]
  41. Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M. 41.  et al. 2012. The mechanism of γ-secretase dysfunction in familial Alzheimer disease. EMBO J. 31:2261–74 [Google Scholar]
  42. Fukumori A, Fluhrer R, Steiner H, Haass C. 42.  2010. Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of γ-secretase-mediated intramembrane proteolysis. J. Neurosci. 30:7853–62 [Google Scholar]
  43. Barret AJ, Rawlings ND, Woessner JF. 43.  2013. Handbook of Proteolytic Enzymes London: Academic, 3rd ed.. [Google Scholar]
  44. Delmarcelle M, Boursoit MC, Filée P, Baurin SL, Frère JM, Joris B. 44.  2005. Specificity inversion of Ochrobactrum anthropi D-aminopeptidase to a D,D-carboxypeptidase with new penicillin binding activity by directed mutagenesis. Protein Sci. 14:2296–303 [Google Scholar]
  45. Wakabayashi T, De Strooper B. 45.  2008. Presenilins: members of the γ-secretase quartets, but part-time soloists too. Physiology 23:194–204 [Google Scholar]
  46. Dickey SW, Baker RP, Cho S, Urban S. 46.  2013. Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity. Cell 155:1270–81 [Google Scholar]
  47. Hébert SS, Serneels L, Dejaegere T, Horré K, Dabrowski M. 47.  et al. 2004. Coordinated and widespread expression of γ-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol. Dis. 17:260–72 [Google Scholar]
  48. Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H. 48.  2004. Identification of distinct γ-secretase complexes with different APH-1 variants. J. Biol. Chem. 279:41340–45 [Google Scholar]
  49. Serneels L, Dejaegere T, Craessaerts K, Horré K, Jorissen E. 49.  et al. 2005. Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc. Natl. Acad. Sci. USA 102:1719–24 [Google Scholar]
  50. Ma G, Li T, Price DL, Wong PC. 50.  2005. APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development. J. Neurosci. 25:192–98 [Google Scholar]
  51. Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A. 51.  1999. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13:2801–10 [Google Scholar]
  52. Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K. 52.  et al. 1999. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc. Natl. Acad. Sci. USA 96:11872–77 [Google Scholar]
  53. Dejaegere T, Serneels L, Schäfer MK, Van Biervliet J, Horré K. 53.  et al. 2008. Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc. Natl. Acad. Sci. USA 105:9775–80 [Google Scholar]
  54. Coolen MW, Van Loo KM, Van Bakel NNMH, Pulford DJ, Serneels L. 54.  et al. 2005. Gene dosage effect on γ-secretase component Aph-1b in a rat model for neurodevelopmental disorders. Neuron 45:497–503 [Google Scholar]
  55. Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horré K. 55.  et al. 2009. γ-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 324:639–42 [Google Scholar]
  56. Best JD, Jay MT, Otu F, Churcher I, Reilly M. 56.  et al. 2006. In vivo characterization of Aβ(40) changes in brain and cerebrospinal fluid using the novel γ-secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the rat. J. Pharmacol. Exp. Ther. 317:786–90 [Google Scholar]
  57. Borgegard T, Gustavsson S, Nilsson C, Parpal S, Klintenberg R. 57.  et al. 2012. Alzheimer's disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aβ peptide-lowering strategy. J. Neurosci. 32:17297–305 [Google Scholar]
  58. Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L. 58.  2013. γ-Secretase inhibitors and modulators. Biochim. Biophys. Acta 1828:2898–907 [Google Scholar]
  59. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B. 59.  et al. 1999. Peptidomimetic probes and molecular modeling suggest that Alzheimer's γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 38:4720–27 [Google Scholar]
  60. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL. 60.  et al. 2000. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat. Cell Biol. 2:428–34 [Google Scholar]
  61. Li YM, Xu M, Lai MT, Huang Q, Castro JL. 61.  et al. 2000. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405:689–94 [Google Scholar]
  62. Kreft AF, Martone R, Porte A. 62.  2009. Recent advances in the identification of γ-secretase inhibitors to clinically test the Aβ oligomer hypothesis of Alzheimer's disease. J. Med. Chem. 52:6169–88 [Google Scholar]
  63. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P. 63.  et al. 2001. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem. 76:173–81 [Google Scholar]
  64. Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y. 64.  et al. 2006. C-terminal fragment of presenilin is the molecular target of a dipeptidic γ-secretase-specific inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester). J. Biol. Chem. 281:14670–76 [Google Scholar]
  65. Kornilova AY, Bihel F, Das C, Wolfe MS. 65.  2005. The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. Proc. Natl. Acad. Sci. USA 102:3230–35 [Google Scholar]
  66. Svedruzic ZM, Popovic K, Sendula-Jengic V. 66.  2013. Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer's disease. PLOS ONE 8:e50759 [Google Scholar]
  67. Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H. 67.  et al. 2012. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J. Neurosci. 32:2037–50 [Google Scholar]
  68. Hyde LA, Zhang Q, Del Vecchio RA, Leach PT, Cohen-Williams ME. 68.  et al. 2013. In vivo characterization of a novel γ-secretase inhibitor SCH 697466 in rodents and investigation of strategies for managing notch-related side effects. Int. J. Alzheimer's Dis. 2013:823528 [Google Scholar]
  69. Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M. 69.  et al. 2012. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 69:1430–40 [Google Scholar]
  70. Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R. 70.  et al. 2013. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J. Pharmacol. Exp. Ther. 344:686–95 [Google Scholar]
  71. Crump CJ, Castro SV, Wang F, Pozdnyakov N, Ballard TE. 71.  et al. 2012. BMS-708,163 targets presenilin and lacks Notch-sparing activity. Biochemistry 51:7209–11 [Google Scholar]
  72. Probst G, Aubele DL, Bowers S, Dressen D, Garofalo AW. 72.  et al. 2013. Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase inhibitors that selectively inhibit the production of amyloid-β over Notch. J. Med. Chem. 56:5261–74 [Google Scholar]
  73. Das C, Berezovska O, Diehl TS, Genet C, Buldyrev I. 73.  et al. 2003. Designed helical peptides inhibit an intramembrane protease. J. Am. Chem. Soc. 125:11794–95 [Google Scholar]
  74. Bihel F, Das C, Bowman MJ, Wolfe MS. 74.  2004. Discovery of a subnanomolar helical d-tridecapeptide inhibitor of γ-secretase. J. Med. Chem. 47:3931–33 [Google Scholar]
  75. Ohki Y, Higo T, Uemura K, Shimada N, Osawa S. 75.  et al. 2011. Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J. 30:4815–24 [Google Scholar]
  76. Extance A. 76.  2010. Alzheimer's failure raises questions about disease-modifying strategies. Nat. Rev. Drug Discov. 9:749–51 [Google Scholar]
  77. Best JD, Smith DW, Reilly MA, O'Donnell R, Lewis HD. 77.  et al. 2007. The novel γ secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethane-sulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of Notch-related pathology in the Tg2576 mouse. J. Pharmacol. Exp. Ther. 320:552–58 [Google Scholar]
  78. Zhao B, Yu M, Neitzel M, Marugg J, Jagodzinski J. 78.  et al. 2008. Identification of γ-secretase inhibitor potency determinants on presenilin. J. Biol. Chem. 283:2927–38 [Google Scholar]
  79. Lee J, Song L, Terracina G, Bara T, Josien H. 79.  et al. 2011. Identification of presenilin 1-selective γ-secretase inhibitors with reconstituted γ-secretase complexes. Biochemistry 50:4973–80 [Google Scholar]
  80. Acx H, Chávez-Gutiérrez L, Serneels L, Lismont S, Benurwar M. 80.  et al. 2013. Signature Aβ profiles are produced by different γ-secretase complexes. J. Biol. Chem. 280:4346–55 [Google Scholar]
  81. Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S. 81.  et al. 2005. Diverse compounds mimic Alzheimer disease–causing mutations by augmenting Aβ42 production. Nat. Med. 11:545–50 [Google Scholar]
  82. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R. 82.  et al. 2001. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414:212–16 [Google Scholar]
  83. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P. 83.  et al. 2003. NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. J. Clin. Investig. 112:440–49 [Google Scholar]
  84. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G. 84.  et al. 2009. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302:2557–64 [Google Scholar]
  85. Ross J, Sharma S, Winston J, Nunez M, Bottini G. 85.  et al. 2013. CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study. Curr. Alzheimer Res. 10:742–53 [Google Scholar]
  86. Crump CJ, Johnson DS, Li YM. 86.  2013. Development and mechanism of γ-secretase modulators for Alzheimer's disease. Biochemistry 52:3197–216 [Google Scholar]
  87. Oehlrich D, Berthelot DJC, Gijsen HJM. 87.  2011. γ-Secretase modulators as potential disease modifying anti-Alzheimer's drugs. J. Med. Chem. 54:669–98 [Google Scholar]
  88. Rogers K, Felsenstein KM, Hrdlicka L, Tu Z, Albayya F. 88.  et al. 2012. Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol. Neurodegener. 7:61 [Google Scholar]
  89. Gijsen HJM, Mercken M. 89.  2012. γ-Secretase modulators: Can we combine potency with safety?. Int. J. Alzheimer's Dis. 2012:295207 [Google Scholar]
  90. Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E. 90.  et al. 2010. Modulation of γ-secretase reduces β-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67:769–80 [Google Scholar]
  91. Wagner SL, Zhang C, Cheng S, Nguyen P, Zhang X. 91.  et al. 2014. Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid β peptide variant and augment the production of multiple carboxy-truncated amyloid β species. Biochemistry 53:702–13 [Google Scholar]
  92. Loureiro RM, Dumin JA, McKee TD, Austin WF, Fuller NO. 92.  et al. 2013. Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models. Alzheimer's Res. Ther. 5:19 [Google Scholar]
  93. Chen F, Eckman EA, Eckman CB. 93.  2006. Reductions in levels of the Alzheimer's amyloid β peptide after oral administration of ginsenosides. FASEB J. 20:1269–71 [Google Scholar]
  94. Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R. 94.  et al. 2008. Substrate-targeting γ-secretase modulators. Nature 453:925–29 [Google Scholar]
  95. Richter L, Munter LM, Ness J, Hildebrand PW, Dasari M. 95.  et al. 2010. Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization. Proc. Natl. Acad. Sci. USA 107:14597–602 [Google Scholar]
  96. Watanabe N, Takagi S, Tominaga A, Tomita T, Iwatsubo T. 96.  2010. Functional analysis of the transmembrane domains of presenilin 1: participation of transmembrane domains 2 and 6 in the formation of initial substrate-binding site of γ-secretase. J. Biol. Chem. 285:19738–46 [Google Scholar]
  97. Crump CJ, Fish BA, Castro SV, Chau DM, Gertsik N. 97.  et al. 2011. Piperidine acetic acid based γ-secretase modulators directly bind to presenilin-1. ACS Chem. Neurosci. 2:705–10 [Google Scholar]
  98. Jumpertz T, Rennhack A, Ness J, Baches S, Pietrzik CU. 98.  et al. 2012. Presenilin is the molecular target of acidic γ-secretase modulators in living cells. PLOS ONE 7:e30484 [Google Scholar]
  99. Ebke A, Luebbers T, Fukumori A, Shirotani K, Haass C. 99.  et al. 2011. Novel γ-secretase enzyme modulators directly target presenilin protein. J. Biol. Chem. 286:37181–86 [Google Scholar]
  100. Pozdnyakov N, Murrey HE, Crump CJ, Pettersson M, Ballard TE. 100.  et al. 2013. γ-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin. J. Biol. Chem. 288:9710–20 [Google Scholar]
  101. Uemura K, Farner KC, Hashimoto T, Nasser-Ghodsi N, Wolfe MS. 101.  et al. 2010. Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site. Nat. Commun. 1:130 [Google Scholar]
  102. Annaert WG, Esselens C, Baert V, Boeve C, Snellings G. 102.  et al. 2001. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 32:579–89 [Google Scholar]
  103. Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY. 103.  et al. 2005. Spatial segregation of γ-secretase and substrates in distinct membrane domains. J. Biol. Chem. 280:25892–900 [Google Scholar]
  104. Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C. 104.  et al. 2006. TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature 440:1208–12 [Google Scholar]
  105. Zhou S, Zhou H, Walian PJ, Jap BK. 105.  2005. CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer's disease amyloid β-peptide production. Proc. Natl. Acad. Sci. USA 102:7499–504 [Google Scholar]
  106. He G, Luo W, Li P, Remmers C, Netzer WJ. 106.  et al. 2010. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 467:95–98 [Google Scholar]
  107. Spasic D, Raemaekers T, Dillen K, Declerck I, Baert V. 107.  et al. 2007. Rer1p competes with APH-1 for binding to nicastrin and regulates γ-secretase complex assembly in the early secretory pathway. J. Cell Biol. 176:629–40 [Google Scholar]
  108. Vetrivel KS, Gong P, Bowen JW, Cheng H, Chen Y. 108.  et al. 2007. Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism. Mol. Neurodegener. 2:4 [Google Scholar]
  109. Hussain I, Fabrègue J, Anderes L, Ousson S, Borlat F. 109.  et al. 2013. The role of γ-secretase activating protein (GSAP) and imatinib in the regulation of γ-secretase activity and amyloid-β generation. J. Biol. Chem. 288:2521–31 [Google Scholar]
  110. Olsson B, Legros L, Guilhot F, Strömberg K, Smith J. 110.  et al. 2014. Imatinib treatment and Aβ42 in humans. Alzheimer's Dement. 10(Suppl.)S374–80 [Google Scholar]
  111. Hyman AA, Simons K. 111.  2012. Beyond oil and water—phase transitions in cells. Science 337:1047–49 [Google Scholar]
  112. Simons K, Sampaio JL. 112.  2011. Membrane organization and lipid rafts. Cold Spring Harb. Perspect. Biol. 3:a004697 [Google Scholar]
  113. Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T. 113.  et al. 2004. Association of γ-secretase with lipid rafts in post-Golgi and endosome membranes. J. Biol. Chem. 279:44945–54 [Google Scholar]
  114. Kakuda N, Shoji M, Arai H, Furukawa K, Ikeuchi T. 114.  et al. 2012. Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease. EMBO Mol. Med. 4:344–52 [Google Scholar]
  115. Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ. 115.  2008. Direct and potent regulation of γ-secretase by its lipid microenvironment. J. Biol. Chem. 283:22529–40 [Google Scholar]
  116. Holmes O, Paturi S, Ye W, Wolfe MS, Selkoe DJ. 116.  2012. Effects of membrane lipids on the activity and processivity of purified γ-secretase. Biochemistry 51:3565–75 [Google Scholar]
  117. Winkler E, Kamp F, Scheuring J, Ebke A, Fukumori A, Steiner H. 117.  2012. Generation of Alzheimer disease-associated amyloid β42/43 peptide by γ-secretase can be inhibited directly by modulation of membrane thickness. J. Biol. Chem. 287:21326–34 [Google Scholar]
  118. Wakabayashi T, Craessaerts K, Bammens L, Bentahir M, Borgions F. 118.  et al. 2009. Analysis of the γ-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat. Cell Biol. 11:1340–46 [Google Scholar]
  119. Yáñez-Mó M, Gutiérrez-López MD, Cabañas C. 119.  2011. Functional interplay between tetraspanins and proteases. Cell Mol. Life Sci. 68:3323–35 [Google Scholar]
  120. Haining EJ, Yang J, Bailey RL, Khan K, Collier R. 120.  et al. 2012. The TspanC8 subgroup of tetraspanins interacts with A disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression. J. Biol. Chem. 287:39753–65 [Google Scholar]
  121. Xu D, Sharma C, Hemler ME. 121.  2009. Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J. 23:3674–81 [Google Scholar]
  122. Dunn CD, Sulis ML, Ferrando AA, Greenwald I. 122.  2010. A conserved tetraspanin subfamily promotes Notch signaling in Caenorhabditis elegans and in human cells. Proc. Natl. Acad. Sci. USA 107:5907–12 [Google Scholar]
  123. Ni Y, Zhao X, Bao G, Zou L, Teng L. 123.  et al. 2006. Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation. Nat. Med. 12:1390–96 [Google Scholar]
  124. Teng L, Zhao J, Wang F, Ma L, Pei G. 124.  2010. A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis. Cell Res. 20:138–53 [Google Scholar]
  125. Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A. 125.  et al. 2009. The orphan G protein–coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science 323:946–51 [Google Scholar]
  126. Liu X, Zhao X, Zeng X, Bossers K, Swaab DF. 126.  et al. 2013. β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology. Cell Res. 23:351–65 [Google Scholar]
  127. Thathiah A, Horré K, Snellinx A, Vandewyer E, Huang Y. 127.  et al. 2013. β-Arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat. Med. 19:43–49 [Google Scholar]
  128. Nelson CD, Sheng M. 128.  2013. Gpr3 stimulates Aβ production via interactions with APP and beta-arrestin2. PLOS ONE 8:e74680 [Google Scholar]
  129. Thathiah A, De Strooper B. 129.  2011. The role of G protein-coupled receptors in the pathology of Alzheimer's disease. Nat. Rev. Neurosci. 12:73–87 [Google Scholar]
  130. Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H. 130.  2006. Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores. Proc. Natl. Acad. Sci. USA. 103:6889–94 [Google Scholar]
  131. Renzi F, Zhang X, Rice WJ, Torres-Arancivia C, Gomez-Llorente Y. 131.  et al. 2011. Structure of γ-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J. Biol. Chem. 286:21440–49 [Google Scholar]
  132. Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R. 132.  et al. 2006. Three-dimensional structure of the γ-secretase complex. Biochem. Biophys. Res. Commun. 343:525–34 [Google Scholar]
  133. Fraering PC, Ye W, Strub JM, Dolios G, LaVoie MJ. 133.  et al. 2004. Purification and characterization of the human γ-secretase complex. Biochemistry 43:9774–89 [Google Scholar]
  134. Alattia JR, Matasci M, Dimitrov M, Aeschbach L, Balasubramanian S. 134.  et al. 2013. Highly efficient production of the Alzheimer's γ-secretase integral membrane protease complex by a multi-gene stable integration approach. Biotechnol. Bioeng. 110:1995–2005 [Google Scholar]
  135. Cacquevel M, Aeschbach L, Osenkowski P, Li D, Ye W. 135.  et al. 2008. Rapid purification of active γ-secretase, an intramembrane protease implicated in Alzheimer's disease. J. Neurochem. 104:210–20 [Google Scholar]
  136. Alattia JR, Schweizer C, Cacquevel M, Dimitrov M, Aeschbach L. 136.  et al. 2012. Generation of monoclonal antibody fragments binding the native γ-secretase complex for use in structural studies. Biochemistry 51:8779–90 [Google Scholar]
  137. Zhang X, Hoey RJ, Lin G, Koide A, Leung B. 137.  et al. 2012. Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies. Proc. Natl. Acad. Sci. USA 109:8534–39 [Google Scholar]
  138. Nelson O, Supnet C, Tolia A, Horré K, De Strooper B, Bezprozvanny I. 138.  2011. Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J. Biol. Chem. 286:22339–47 [Google Scholar]
  139. Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. 139.  2002. Identification of a novel family of presenilin homologues. Hum. Mol. Genet. 11:1037–44 [Google Scholar]
  140. Liao M, Cao E, Julius D, Cheng Y. 140.  2013. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504:107–12 [Google Scholar]
  141. Cao E, Liao M, Cheng Y, Julius D. 141.  2013. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504:113–18 [Google Scholar]
  142. Peilo GL, Xiao-chen B, Dan M, Tian X, Chuangye Y. 142.  et al. 2014. Three dimensional structure of human γ-secretase. Nature 512:166–70 [Google Scholar]
  143. Chávez-Gutiérrez L, Tolia A, Maes E, Li T, Wong PC, de Strooper B. 143.  2008. Glu332 in the Nicastrin ectodomain is essential for γ-secretase complex maturation but not for its activity. J. Biol. Chem. 283:20096–105 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error