Learning by failing: Ideas and concepts to tackle γ-secretases in Alzheimer's disease and beyond

Annual Review of Pharmacology and Toxicology

Volumn 55, Issue , 2015, Pages 419-437

  De Strooper, Bart ^a,b   Chávez Gutiérrez, Lucía ^a,b  

^a DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

^b UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

Clinical trials; Intramembrane proteolysis; Modulators; Structure; Therapy

Indexed keywords

3 [(3 CHOLAMIDOPROPYL)DIMETHYLAMMONIO] 2 HYDROXY 1 PROPANESULFONIC ACID; AMINOPEPTIDASE; AVAGACESTAT; BAPINEUZUMAB; BEGACESTAT; BMS 299897; ELND 006; FLURBIPROFEN; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; GINSENOSIDE; GSM 1; L 685458; NONSTEROID ANTIINFLAMMATORY AGENT; PRESENILIN; PROTEASOME; R 0 57; SCH 1500022; SCH 697466; SEMAGACESTAT; SOLANEZUMAB; TETRASPANIN; UNCLASSIFIED DRUG; ALANINE; AMYLOID PRECURSOR PROTEIN; AZEPINE DERIVATIVE; N2-((2S)-2-(3,5-DIFLUOROPHENYL)-2-HYDROXYETHANOYL)-N1-((7S)-5-METHYL-6-OXO-6,7-DIHYDRO-5H-DIBENZO(B,D)AZEPIN-7-YL)-L-ALANINAMIDE; PROTEINASE INHIBITOR; SECRETASE;

ALZHEIMER DISEASE; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN; LIPID MEMBRANE; LIVER TOXICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN DEGRADATION; REVIEW; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; ENZYME SPECIFICITY; ENZYMOLOGY; METABOLISM; MOLECULARLY TARGETED THERAPY; PROCEDURES; STRUCTURE ACTIVITY RELATION; TREATMENT FAILURE;

ALANINE; ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN PRECURSOR; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; AZEPINES; DRUG DESIGN; HUMANS; MOLECULAR STRUCTURE; MOLECULAR TARGETED THERAPY; PROTEASE INHIBITORS; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY; TREATMENT FAILURE;

EID: 84920771964     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-010814-124309     Document Type: Review

References (143)

1. Karran E, Mercken M, De Strooper B. 2011. The amyloid cascade hypothesis for Alzheimers disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10:698-712
2. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, et al. 2012. Clinical and biomarker changes in dominantly inherited Alzheimers disease. N. Engl. J. Med. 367:795-804
3. Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, et al. 2013. Preclinical Alzheimers disease and its outcome: A longitudinal cohort study. Lancet Neurol. 12:957-65
4. De Strooper B. 2010. Proteases and proteolysis in Alzheimer disease: A multifactorial view on the disease process. Physiol. Rev. 90:465-94
5. Karran E, Hardy J. 2014. Antiamyloid therapy for Alzheimers disease-are we on the right road? N. Engl. J. Med. 370:377-78
6. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, et al. 2014. Phase 3 trials of solanezumab for mild-to-moderate Alzheimers disease. N. Engl. J. Med. 370:311-21
7. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, et al. 2014. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimers disease. N. Engl. J. Med. 370:322-33
8. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, et al. 2013. A phase 3 trial of semagacestat for treatment of Alzheimers disease. N. Engl. J. Med. 369:341-50
9. Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U, et al. 2012. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 31:3157-68
10. Zhou L, Barao S, Laga M, Bockstael K, Borgers M, et al. 2012. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J. Biol. Chem. 287:25927-40
11. Rochin L, Hurbain I, Serneels L, Fort C, Watt B, et al. 2013. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc. Natl. Acad. Sci. USA 110:10658-63
12. Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, et al. 2013. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 32:2015-28
13. Jurisch-Yaksi N, Sannerud R, Annaert W. 2013. A fast growing spectrum of biological functions of γ-secretase in development and disease. Biochim. Biophys. Acta 1828:2815-27
14. Clark RF, Hutton M, Fuldner M, Froelich S, Karran E, 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
15. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, et al. 1995. Candidate gene for the chromosome 1 familial Alzheimers disease locus. Science 269:973-77
16. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, et al. 1995. Familial Alzheimers disease in kindreds with missensemutations in a gene on chromosome 1 related to the Alzheimers disease type 3 gene. Nature 376:775-78
17. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, et al. 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimers disease. Nature 375:754-60
18. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, et al. 1998. Deficiency of presenilin- 1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387-90
19. DeStrooper B. 2003. Aph-1, Pen-2, andNicastrin with Presenilin generate an activeγ-secretase complex. Neuron 38:9-12
20. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. 1999. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398:513-17
21. Hayashi I, Urano Y, Fukuda R, Isoo N, Kodama T, et al. 2004. Selective reconstitution and recovery of functional γ-secretase complex on budded baculovirus particles. J. Biol. Chem. 279:38040-46
22. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. 2003. Reconstitution of γ-secretase activity. Nat. Cell Biol. 5:486-88
23. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. 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
24. Osenkowski P, Li H, Ye W, Li D, Aeschbach L, et al. 2009. Cryoelectron microscopy structure of purified γ-secretase at 12Å resolution. J. Mol. Biol. 385:642-52
25. Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y, et al. 2007. Active γ-secretase complexes contain only one of each component. J. Biol. Chem. 282:33985-93
26. Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ III. 2013. Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβproduction. J. Neurosci. 33:11606-17
27. Schroeter EH, Ilagan MXG, Brunkan AL, Hecimovic S, Li YM, 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
28. Erez E, Fass D, Bibi E. 2009. How intramembrane proteases bury hydrolytic reactions in themembrane. Nature 459:371-78
29. Tolia A, Chavez-Gutierrez L, De Strooper B. 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
30. Sato C, Morohashi Y, Tomita T, Iwatsubo T. 2006. Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. J. Neurosci. 26:12081-88
31. Tolia A, Horre K, De Strooper B. 2008. Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of γ-secretase. J. Biol. Chem. 283:19793-803
32. Sato C, Takagi S, Tomita T, Iwatsubo T. 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
33. Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo T. 2010. Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase. J. Neurosci. 30:15943-50
34. Li X, Dang S, Yan C, Gong X, Wang J, Shi Y. 2013. Structure of a presenilin family intramembrane aspartate protease. Nature 493:56-61
35. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, et al. 2009. γ-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of β-carboxyl terminal fragment. J. Neurosci. 29:13042-52
36. Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, et al. 2003. Potential link between amyloid β-protein 42 and C-terminal fragment γ49-99 of β-amyloid precursor protein. J. Biol. Chem. 278:24294-301
37. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, et al. 2005. Longer forms of amyloid β protein: implications for the mechanism of intramembrane cleavage by γ-secretase. J. Neurosci. 25:436-45
38. Kakuda N, Funamoto S, Yagishita S, Takami M, Osawa S, et al. 2006. Equimolar production of amyloid β-protein and amyloid precursor protein intracellular domain from β-carboxyl-terminal fragment by γ-secretase. J. Biol. Chem. 281:14776-86
39. Yagishita S, Morishima-Kawashima M, Ishiura S, Ihara Y. 2008. Aβ46 is processed to Aβ40 and Aβ43, but not to Aβ42, in the low density membrane domains. J. Biol. Chem. 283:733-38
40. Matsumura N, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H, et al. 2014. γ-Secretase associated with lipid rafts:multiple interactive pathways in the stepwise processing ofβ-carboxyl terminal fragment. J. Biol. Chem. 289:5109-21
41. Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, et al. 2012. The mechanism of γ-secretase dysfunction in familial Alzheimer disease. EMBO J. 31:2261-74
42. Fukumori A, Fluhrer R, Steiner H, Haass C. 2010. Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of γ-secretase-mediated intramembrane proteolysis. J. Neurosci. 30:7853-62
43. Barret AJ, Rawlings ND, Woessner JF. 2013. Handbook of Proteolytic Enzymes. London: Academic. 3rd ed.
44. Delmarcelle M, Boursoit MC, Filee P, Baurin SL, Frere JM, Joris B. 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
45. Wakabayashi T, De Strooper B. 2008. Presenilins: members of the γ-secretase quartets, but part-time soloists too. Physiology 23:194-204
46. Dickey SW, Baker RP, Cho S, Urban S. 2013. Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity. Cell 155:1270-81
47. Hebert SS, Serneels L, Dejaegere T, Horre K, Dabrowski M, et al. 2004. Coordinated and widespread expression ofγ-secretase in vivo: evidence for size andmolecular heterogeneity. Neurobiol. Dis. 17:260-72
48. Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H. 2004. Identification of distinct γ-secretase complexes with different APH-1 variants. J. Biol. Chem. 279:41340-45
49. Serneels L, Dejaegere T, Craessaerts K, Horre K, Jorissen E, et al. 2005. Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc. Natl. Acad. Sci. USA 102:1719-24
50. Ma G, Li T, Price DL, Wong PC. 2005. APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development. J. Neurosci. 25:192-98
51. Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A. 1999. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13:2801-10
52. Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, 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
53. Dejaegere T, Serneels L, Schafer MK, Van Biervliet J, Horre K, 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
54. Coolen MW, Van Loo KM, Van Bakel NNMH, Pulford DJ, Serneels L, et al. 2005. Gene dosage effect on γ-secretase component Aph-1b in a rat model for neurodevelopmental disorders. Neuron 45:497-503
55. Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horre K, et al. 2009. γ-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimers disease. Science 324:639-42
56. Best JD, Jay MT, Otu F, Churcher I, Reilly M, et al. 2006. In vivo characterization of Aβ (40) changes in brain and cerebrospinal fluid using the novelγ-secretase inhibitorN-[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
57. Borgegard T, Gustavsson S, Nilsson C, Parpal S, Klintenberg R, et al. 2012. Alzheimers disease: presenilin 2-sparing γ-secretase inhibition is a tolerable A? peptide-lowering strategy. J. Neurosci. 32:17297-305
58. Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L. 2013. γ-Secretase inhibitors and modulators. Biochim. Biophys. Acta 1828:2898-907
59. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, et al. 1999. Peptidomimetic probes and molecular modeling suggest that Alzheimers γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 38:4720-27
60. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, et al. 2000. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat. Cell Biol. 2:428-34
61. Li YM, Xu M, Lai MT, Huang Q, Castro JL, et al. 2000. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405:689-94
62. Kreft AF, Martone R, Porte A. 2009. Recent advances in the identification of γ-secretase inhibitors to clinically test the Aβoligomer hypothesis of Alzheimers disease. J. Med. Chem. 52:6169-88
63. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, et al. 2001. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem. 76:173-81
64. Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y, et al. 2006. C-terminal fragment of presenilin is themolecular target of a dipeptidicγ-secretase-specific inhibitorDAPT(N-[N-(3, 5-difluorophenacetyl)- L-alanyl]-S-phenylglycine t-butyl ester). J. Biol. Chem. 281:14670-76
65. Kornilova AY, Bihel F, Das C, Wolfe MS. 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
66. Svedruzic ZM, Popovic K, Sendula-Jengic V. 2013. Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimers disease. PLOS ONE 8:e50759
67. Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H, 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
68. Hyde LA, Zhang Q, Del Vecchio RA, Leach PT, Cohen-Williams ME, 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. Alzheimers Dis. 2013:823528
69. Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, 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
70. Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R, et al. 2013. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J. Pharmacol. Exp. Ther. 344:686-95
71. Crump CJ, Castro SV, Wang F, Pozdnyakov N, Ballard TE, et al. 2012. BMS-708, 163 targets presenilin and lacks Notch-sparing activity. Biochemistry 51:7209-11
72. Probst G, Aubele DL, Bowers S, Dressen D, Garofalo AW, 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
73. Das C, Berezovska O, Diehl TS, Genet C, Buldyrev I, et al. 2003. Designed helical peptides inhibit an intramembrane protease. J. Am. Chem. Soc. 125:11794-95
74. Bihel F, Das C, Bowman MJ, Wolfe MS. 2004. Discovery of a subnanomolar helical D-tridecapeptide inhibitor of γ-secretase. J. Med. Chem. 47:3931-33
75. Ohki Y, Higo T, Uemura K, Shimada N, Osawa S, et al. 2011. Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J. 30:4815-24
76. Extance A. 2010. Alzheimers failure raises questions about disease-modifying strategies. Nat. Rev. Drug Discov. 9:749-51
77. Best JD, Smith DW, Reilly MA, ODonnell R, Lewis HD, et al. 2007. The novel γ secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2, 5-difluorophenyl)cyclohexyl]-1, 1, 1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of Notch-related pathology in the Tg2576 mouse. J. Pharmacol. Exp. Ther. 320:552-58
78. Zhao B, Yu M, Neitzel M, Marugg J, Jagodzinski J, et al. 2008. Identification of γ-secretase inhibitor potency determinants on presenilin. J. Biol. Chem. 283:2927-38
79. Lee J, Song L, Terracina G, Bara T, Josien H, et al. 2011. Identification of presenilin 1-selective γ-secretase inhibitors with reconstituted γ-secretase complexes. Biochemistry 50:4973-80
80. Acx H, Chavez-Gutierrez L, Serneels L, Lismont S, Benurwar M, et al. 2013. Signature Aβprofiles are produced by different γ-secretase complexes. J. Biol. Chem. 280:4346-55
81. Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, et al. 2005. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nat. Med. 11:545-50
82. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, et al. 2001. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414:212-16
83. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, et al. 2003. NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. J. Clin. Investig. 112:440-49
84. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, 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
85. Ross J, Sharma S, Winston J, Nunez M, Bottini G, 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
86. Crump CJ, Johnson DS, Li YM. 2013. Development and mechanism of γ-secretase modulators for Alzheimers disease. Biochemistry 52:3197-216
87. Oehlrich D, Berthelot DJC, Gijsen HJM. 2011. γ-Secretase modulators as potential disease modifying anti-Alzheimers drugs. J. Med. Chem. 54:669-98
88. Rogers K, Felsenstein KM, Hrdlicka L, Tu Z, Albayya F, et al. 2012. Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol. Neurodegener. 7:61
89. Gijsen HJM, Mercken M. 2012. γ-Secretase modulators: Can we combine potency with safety? Int. J. Alzheimers Dis. 2012:295207
90. Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E, et al. 2010. Modulation ofγ-secretase reduces β-amyloid deposition in a transgenic mouse model of Alzheimers disease. Neuron 67:769-80
91. Wagner SL, Zhang C, Cheng S, Nguyen P, Zhang X, 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
92. Loureiro RM, Dumin JA, McKee TD, Austin WF, Fuller NO, et al. 2013. Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models. Alzheimers Res. Ther. 5:19
93. Chen F, Eckman EA, Eckman CB. 2006. Reductions in levels of the Alzheimers amyloid β peptide after oral administration of ginsenosides. FASEB J. 20:1269-71
94. Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R, et al. 2008. Substrate-targeting γ-secretase modulators. Nature 453:925-29
95. Richter L, Munter LM, Ness J, Hildebrand PW, Dasari M, et al. 2010. Amyloid beta 42 peptide (A42)- lowering compounds directly bind to A and interfere with amyloid precursor protein (APP) transmembrane dimerization. Proc. Natl. Acad. Sci. USA 107:14597-602
96. Watanabe N, Takagi S, Tominaga A, Tomita T, Iwatsubo T. 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
97. Crump CJ, Fish BA, Castro SV, Chau DM, Gertsik N, et al. 2011. Piperidine acetic acid basedγ-secretase modulators directly bind to presenilin-1. ACS Chem. Neurosci. 2:705-10
98. Jumpertz T, Rennhack A, Ness J, Baches S, Pietrzik CU, et al. 2012. Presenilin is the molecular target of acidic γ-secretase modulators in living cells. PLOS ONE 7:e30484
99. Ebke A, Luebbers T, Fukumori A, Shirotani K, Haass C, et al. 2011. Novel γ-secretase enzyme modulators directly target presenilin protein. J. Biol. Chem. 286:37181-86
100. Pozdnyakov N, Murrey HE, Crump CJ, Pettersson M, Ballard TE, et al. 2013. γ-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin. J. Biol. Chem. 288:9710-20
101. Uemura K, Farner KC, Hashimoto T, Nasser-Ghodsi N, Wolfe MS, et al. 2010. Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site. Nat. Commun. 1:130
102. Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, et al. 2001. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 32:579-89
103. Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, et al. 2005. Spatial segregation of γ-secretase and substrates in distinct membrane domains. J. Biol. Chem. 280:25892-900
104. Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, et al. 2006. TMP21 is a presenilin complex component that modulates γ-secretase but not γ-secretase activity. Nature 440:1208-12
105. Zhou S, Zhou H, Walian PJ, Jap BK. 2005. CD147 is a regulatory subunit of the γ-secretase complex in Alzheimers disease amyloid β-peptide production. Proc. Natl. Acad. Sci. USA 102:7499-504
106. He G, Luo W, Li P, Remmers C, Netzer WJ, et al. 2010. Gamma-secretase activating protein is a therapeutic target for Alzheimers disease. Nature 467:95-98
107. Spasic D, Raemaekers T, Dillen K, Declerck I, Baert V, 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
108. Vetrivel KS, Gong P, Bowen JW, Cheng H, Chen Y, et al. 2007. Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism. Mol. Neurodegener. 2:4
109. Hussain I, Fabregue J, Anderes L, Ousson S, Borlat F, 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
110. Olsson B, Legros L, Guilhot F, Str omberg K, Smith J, et al. 2014. Imatinib treatment and Aβ42 in humans. Alzheimers Dement. 10(Suppl.):S374-80
111. Hyman AA, Simons K. 2012. Beyond oil and water-phase transitions in cells. Science 337:1047-49
112. Simons K, Sampaio JL. 2011. Membrane organization and lipid rafts. Cold Spring Harb. Perspect. Biol. 3:a004697
113. Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, et al. 2004. Association of γ-secretase with lipid rafts in post-Golgi and endosome membranes. J. Biol. Chem. 279:44945-54
114. Kakuda N, Shoji M, Arai H, Furukawa K, Ikeuchi T, et al. 2012. Altered γ-secretase activity in mild cognitive impairment and Alzheimers disease. EMBO Mol. Med. 4:344-52
115. Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ. 2008. Direct and potent regulation of γ-secretase by its lipid microenvironment. J. Biol. Chem. 283:22529-40
116. Holmes O, Paturi S, Ye W, Wolfe MS, Selkoe DJ. 2012. Effects of membrane lipids on the activity and processivity of purified γ-secretase. Biochemistry 51:3565-75
117. Winkler E, Kamp F, Scheuring J, Ebke A, Fukumori A, Steiner H. 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
118. Wakabayashi T, Craessaerts K, Bammens L, Bentahir M, Borgions F, et al. 2009. Analysis of the γ-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat. Cell Biol. 11:1340-46
119. Yanez-Mo M, Gutierrez-Lopez MD, Cabanas C. 2011. Functional interplay between tetraspanins and proteases. Cell Mol. Life Sci. 68:3323-35
120. Haining EJ, Yang J, Bailey RL, Khan K, Collier R, 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
121. Xu D, Sharma C, Hemler ME. 2009. Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J. 23:3674-81
122. Dunn CD, Sulis ML, Ferrando AA, Greenwald I. 2010. A conserved tetraspanin subfamily promotes Notch signaling in Caenorhabditis elegans and in human cells. Proc. Natl. Acad. Sci. USA 107:5907-12
123. Ni Y, Zhao X, Bao G, Zou L, Teng L, et al. 2006. Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation. Nat. Med. 12:1390-96
124. Teng L, Zhao J, Wang F, Ma L, Pei G. 2010. A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβproduction and contributes to AD pathogenesis. Cell Res. 20:138-53
125. Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, et al. 2009. The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science 323:946-51
126. Liu X, Zhao X, Zeng X, Bossers K, Swaab DF, et al. 2013. β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology. Cell Res. Cell Res. 23:351-65
127. Thathiah A, Horre K, Snellinx A, Vandewyer E, Huang Y, et al. 2013. β-Arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimers disease. Nat. Med. 19:43-49
128. Nelson CD, Sheng M. 2013. Gpr3 stimulates Aβ production via interactions with APP and betaarrestin2. PLOS ONE 8:e74680
129. Thathiah A, De Strooper B. 2011. The role of G protein-coupled receptors in the pathology of Alzheimers disease. Nat. Rev. Neurosci. 12:73-87
130. Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H. 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
131. Renzi F, Zhang X, Rice WJ, Torres-Arancivia C, Gomez-Llorente Y, et al. 2011. Structure of γ-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J. Biol. Chem. 286:21440-49
132. Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, et al. 2006. Three-dimensional structure of the γ-secretase complex. Biochem. Biophys. Res. Commun. 343:525-34
133. Fraering PC, Ye W, Strub JM, Dolios G, LaVoie MJ, et al. 2004. Purification and characterization of the human γ-secretase complex. Biochemistry 43:9774-89
134. Alattia JR, Matasci M, Dimitrov M, Aeschbach L, Balasubramanian S, et al. 2013. Highly efficient production of the Alzheimers γ-secretase integral membrane protease complex by a multi-gene stable integration approach. Biotechnol. Bioeng. 110:1995-2005
135. Cacquevel M, Aeschbach L, Osenkowski P, Li D, Ye W, et al. 2008. Rapid purification of active γ-secretase, an intramembrane protease implicated in Alzheimers disease. J. Neurochem. 104:210-20
136. Alattia JR, Schweizer C, Cacquevel M, Dimitrov M, Aeschbach L, et al. 2012. Generation of monoclonal antibody fragments binding the native γ-secretase complex for use in structural studies. Biochemistry 51:8779-90
137. Zhang X, Hoey RJ, Lin G, Koide A, Leung B, 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
138. Nelson O, Supnet C, Tolia A, Horre K, De Strooper B, Bezprozvanny I. 2011. Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J. Biol. Chem. 286:22339-47
139. Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. 2002. Identification of a novel family of presenilin homologues. Hum. Mol. Genet. 11:1037-44
140. Liao M, Cao E, Julius D, Cheng Y. 2013. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504:107-12
141. Cao E, Liao M, Cheng Y, Julius D. 2013. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504:113-18
142. Peilo GL, Xiao-chen B, Dan M, Tian X, Chuangye Y, et al. 2014. Three dimensional structure of human γ-secretase. Nature 512:166-70
143. Chavez-Gutierrez L, Tolia A, Maes E, Li T, Wong PC, de Strooper B. 2008. Glu332 in the Nicastrin ectodomain is essential for γ-secretase complex maturation but not for its activity. J. Biol. Chem. 283:20096-105