Presenilin and γ-secretase activity: A viable therapeutic target for Alzheimer's disease?

Current Signal Transduction Therapy

Volumn 5, Issue 2, 2010, Pages 128-140

  Yan, Run ^a   McCarthy, Justin V ^a  

^a UNIVERSITY COLLEGE CORK   (Ireland)

Author keywords

Alzheimer's disease; Amyloid beta (A ); Gamma secretase; Post translational modification; Presenilin; Regulated intramembrane proteolysis

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; BEGACESTAT; BMS 708163; DONEPEZIL; E 2012; GALANTAMINE; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; MEMANTINE; MK 0752; NICASTRIN; NOTCH RECEPTOR; PF 3084014; PLACEBO; PRESENILIN; PRESENILIN 1; PRESENILIN 2; RAZADYNE ER; RIVAMER; RIVASMINE; RIVASTIGMINE; SEMAGACESTAT; TACRINE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ARTICLE; CLINICAL TRIAL; DRUG ACTIVITY; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; DRUG TARGETING; ENZYME ACTIVE SITE; ENZYME ACTIVITY; GENE MUTATION; GENETIC VARIABILITY; GLYCOSYLATION; HUMAN; HYDROPHILICITY; HYDROPHOBICITY; NONHUMAN; PALMITOYLATION; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PURIFICATION; SIGNAL TRANSDUCTION; UBIQUITINATION;

EID: 77953347678     PISSN: 15743624     EISSN: None     Source Type: Journal    
DOI: 10.2174/157436210791112217     Document Type: Article

References (159)

1. Nunan J, Small DH. Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett 2000; 483: 6-10.
2. Haass C, Selkoe DJ. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 1993; 75: 1039-42.
3. Citron M, Teplow DB, Selkoe DJ. Generation of amyloid beta protein from its precursor is sequence specific. Neuron 1995; 14: 661-70.
4. Weidemann A, Eggert S, Reinhard FB, et al. A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 2002; 41: 2825-35.
5. Ghosh AK, Gemma S, Tang J. beta-Secretase as a therapeutic target for Alzheimer's disease. Neurotherapeutics 2008; 5: 399-408.
6. Wolfe MS. Gamma-secretase: structure, function, and modulation for Alzheimer's disease. Curr Top Med Chem 2008; 8: 2-8.
7. Wolfe MS. gamma-Secretase in biology and medicine. Semin Cell Dev Biol 2009, 20: 219-24.
8. Ghosh AK, Kumaragurubaran N, Tang J. Recent developments of structure based beta-secretase inhibitors for Alzheimer's disease. Curr Top Med Chem 2005; 5: 1609-22.
9. Ohno M, Sametsky EA, Younkin LH, et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 2004; 41: 27-33.
10. Harrison SM, Harper AJ, Hawkins J, et al. BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci 2003; 24: 646-55.
11. Willem M, Garratt AN, Novak B, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 2006; 314: 664-6.
12. Ghosh AK, Hong L, Tang J. beta-Secretase as a Therapeutic Target for Inhibitor Drugs. Curr Med Chem 2002; 9: 1135-44.
13. Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000; 290: 150-3.
14. Hong L, Turner RT, 3rd, Koelsch G, Shin D, Ghosh AK, Tang J. Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3. Biochemistry 2002; 41: 10963-7.
15. Tolia A, De Strooper B. Structure and function of gamma-secretase. Semin Cell Dev Biol 2009; 20: 211-8.
16. Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999; 402: 537-40.
17. Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 1999; 402: 533-7.
18. Boulton ME, Cai J, Grant MB. gamma-Secretase: a multifaceted regulator of angiogenesis. J Cell Mol Med 2008; 12: 781-95.
19. McCarthy JV, Twomey C, Wujek P. Presenilin-dependent regulated intramembrane proteolysis and gamma-secretase activity. Cell Mol Life Sci 2009; 66: 1534-55.
20. Lleo A. Activity of gamma-secretase on substrates other than APP. Curr Top Med Chem 2008; 8: 9-16.
21. Hutton M, Hardy J. The presenilins and Alzheimer's disease. Hum Mol Genet 1997; 6: 1639-46.
22. De Strooper B. Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 2007; 8: 141-6.
23. De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391: 387-90.
24. Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2000; 2: 461-2.
25. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci USA 2003; 100: 6382-7.
26. Li YM, Lai MT, Xu M, et al. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci USA 2000; 97: 6138-43.
27. Li YM, Xu M, Lai MT, et al. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000; 405: 689-94.
28. Esler WP, Kimberly WT, Ostaszewski BL, et al. Activity-dependent isolation of the presenilingamma -secretase complex reveals nicastrin and a gamma substrate. Proc Natl Acad Sci USA 2002; 99: 2720-5.
29. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol 2003; 5: 486-8.
30. De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003; 38: 9-12.
31. Fraering PC, Ye W, Strub JM, et al. Purification and characterization of the human gamma-secretase complex. Biochemistry 2004; 43: 9774-89.
32. Fraering PC, LaVoie MJ, Ye W, et al. Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. Biochemistry 2004; 43: 323-33.
33. Winkler E, Hobson S, Fukumori A, et al. Purification, Pharmacological Modulation, and Biochemical Characterization of Interactors of Endogenous Human gamma-Secretase (dagger). Biochemistry 2009; 48: 1183-97.
34. Sato T, Diehl TS, Narayanan S, et al. Active gamma-secretase complexes contain only one of each component. J Biol Chem 2007; 282: 33985-93
35. Hebert SS, Serneels L, Dejaegere T, et al. Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol Dis 2004; 17: 260-72.
36. Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H. Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 2004; 279: 41340-5.
37. Shirotani K, Tomioka M, Kremmer E, Haass C, Steiner H. Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexes. Neurobiol Dis 2007; 27: 102-7.
38. Ma G, Li T, Price DL, Wong PC. APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. J Neurosci 2005; 25: 192-8.
39. Lai MT, Chen E, Crouthamel MC, et al. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem 2003; 278: 22475-81.
40. Serneels L, Dejaegere T, Craessaerts K, et al. Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc Natl Acad Sci USA 2005; 102: 1719-24.
41. Dejaegere T, Serneels L, Schafer MK, et al. Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc Natl Acad Sci USA 2008; 105: 9775-80.
42. Serneels L, Van Biervliet J, Craessaerts K, et al. {gamma}-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease. Science 2009; 324: 639-42.
43. Twomey C, McCarthy JV. Presenilin-1 is an unprimed glycogen synthase kinase-3beta substrate. FEBS Lett 2006; 580: 4015-20.
44. Kirschenbaum F, Hsu SC, Cordell B, McCarthy JV. Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J Biol Chem 2001; 276: 30701-7.
45. Kirschenbaum F, Hsu SC, Cordell B, McCarthy JV. Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling. J Biol Chem 2001; 276: 7366-75.
46. Yu G, Nishimura M, Arawaka S, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000; 407: 48-54.
47. Yang DS, Tandon A, Chen F, et al. Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. J Biol Chem. 2002; 277: 28135-42.
48. Tomita T, Katayama R, Takikawa R, Iwatsubo T. Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments. FEBS Lett 2002; 520: 117-21.
49. Morais VA, Brito C, Pijak DS, et al. N-glycosylation of human nicastrin is required for interaction with the lectins from the secretory pathway calnexin and ERGIC-53. Biochim Biophys Acta 2006; 1762: 802-10.
50. Cheng H, Vetrivel KS, Drisdel RC, et al. S-palmitoylation of gamma-secretase subunits nicastrin and APH-1. J Biol Chem 2009; 284: 1373-84.
51. Massey LK, Mah AL, Monteiro MJ. Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. Biochem J 2005; 391: 513-25.
52. Li J, Pauley AM, Myers RL, et al. SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production. J Neurochem 2002; 82: 1540-8.
53. Kim TW, Pettingell WH, Hallmark OG, Moir RD, Wasco W, Tanzi RE. Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. J Biol Chem 1997; 272: 11006-10.
54. Tesco G, Kim TW, Diehlmann A, Beyreuther K, Tanzi RE. Abrogation of the presenilin 1/beta-catenin interaction and preservation of the heterodimeric presenilin 1 complex following caspase activation. J Biol Chem 1998; 273: 33909-14.
55. Grunberg J, Walter J, Loetscher H, Deuschle U, Jacobsen H, Haass C. Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the caspase family. Biochemistry 1998; 37: 2263-70.
56. Vito P, Ghayur T, D'Adamio L. Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage. J Biol Chem 1997; 272: 28315-20.
57. Henricson A, Kall L, Sonnhammer EL. A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence. FEBS J 2005; 272: 2727-33.
58. Laudon H, Hansson EM, Melen K, et al. A nine-transmembrane domain topology for presenilin 1. J Biol Chem 2005; 280: 35352-60.
59. Ratovitski T, Slunt HH, Thinakaran G, Price DL, Sisodia SS, Borchelt DR. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem 1997; 272: 24536-41.
60. Steiner H, Romig H, Pesold B, et al. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis. Biochemistry 1999; 38: 14600-5.
61. Steiner H, Romig H, Grim MG, et al. The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem 1999; 274: 7615-8.
62. Jacobsen H, Reinhardt D, Brockhaus M, et al. The influence of endoproteolytic processing of familial Alzheimer's disease presenilin 2 on abeta42 amyloid peptide formation. J Biol Chem 1999; 274: 35233-9.
63. Barakat A, Mercer B, Cooper E, Chung HM. Examining requirement for formation of functional Presenilin proteins and their processing events in vivo. Genesis 2009; 47: 161-8.
64. Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science 1997; 277: 373-6.
65. Loetscher H, Deuschle U, Brockhaus M, et al. Presenilins are processed by caspase-type proteases. J Biol Chem. 1997; 272: 20655-9.
66. Alves da Costa C, Paitel E, Mattson MP, et al. Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons. Proc Natl Acad Sci USA 2002; 99: 4043-8.
67. Janicki S, Monteiro MJ. Increased apoptosis arising from increased expression of the Alzheimer's disease-associated presenilin-2 mutation (N141I). J Cell Biol 1997; 139: 485-95.
68. Janicki SM, Stabler SM, Monteiro MJ. Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging 2000; 21: 829-36.
69. Kaether C, Capell A, Edbauer D, et al. The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J 2004; 23(24): 4738-48.
70. Bergman A, Laudon H, Winblad B, Lundkvist J, Naslund J. The extreme C terminus of presenilin 1 is essential for gamma-secretase complex assembly and activity. J Biol Chem 2004; 279: 45564-72.
71. Wang J, Beher D, Nyborg AC, Shearman MS, Golde TE, Goate A. C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. J Neurochem 2006; 96: 218-27.
72. Morais VA, Crystal AS, Pijak DS, et al. The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex. J Biol Chem 2003; 278: 43284-91.
73. Capell A, Beher D, Prokop S, et al. Gamma-secretase complex assembly within the early secretory pathway. J Biol Chem 2005; 280: 6471-8.
74. Niimura M, Isoo N, Takasugi N, et al. Aph-1 contributes to the stabilization and trafficking of the gamma-secretase complex through mechanisms involving intermolecular and intramolecular interactions. J Biol Chem 2005; 280: 12967-75.
75. Lee SF, Shah S, Yu C, et al. A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J Biol Chem 2004; 279: 4144-52.
76. Araki W, Saito S, Takahashi-Sasaki N, Shiraishi H, Komano H, Murayama KS. Characterization of APH-1 mutants with a disrupted transmembrane GxxxG motif. J Mol Neurosci 2006; 29: 35-43.
77. Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T. Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 2005; 280: 41967-75.
78. Kornilova AY, Bihel F, Das C, Wolfe MS. The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. Proc Natl Acad Sci USA 2005; 102: 3230-5.
79. Crystal AS, Morais VA, Pierson TC, et al. Membrane topology of gamma-secretase component PEN-2. J Biol Chem 2003; 278: 20117-23.
80. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999; 398: 513-7.
81. Steiner H, Kostka M, Romig H, et al. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat Cell Biol 2000; 2: 848-51.
82. Tolia A, Chavez-Gutierrez L, De Strooper B. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma-secretase complex. J Biol Chem 2006; 281: 27633-42.
83. Tolia A, Horre K, De Strooper B. Transmembrane Domain 9 of Presenilin Determines the Dynamic Conformation of the Catalytic Site of {gamma}-Secretase. J Biol Chem 2008; 283: 19793-803.
84. Dries DR, Yu G. Assembly, maturation, and trafficking of the gamma-secretase complex in Alzheimer's disease. Curr Alzheimer Res 2008; 5: 132-46.
85. Walter J, Grunberg J, Schindzielorz A, Haass C. Proteolytic fragments of the Alzheimer's disease associated presenilins-1 and -2 are phosphorylated in vivo by distinct cellular mechanisms. Biochemistry 1998; 37: 5961-7.
86. Walter J, Capell A, Grunberg J, et al. The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med. 1996; 2(6): 673-91.
87. Walter J, Grunberg J, Capell A, et al. Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proc Natl Acad Sci USA 1997; 94: 5349-54.
88. Lau KF, Howlett DR, Kesavapany S, et al. Cyclin-Dependent Kinase-5/p35 Phosphorylates Presenilin 1 to Regulate Carboxy-Terminal Fragment Stability. Mol Cell Neurosci 2002; 20: 13-20.
89. Prager K, Wang-Eckhardt L, Fluhrer R, et al. A structural switch of presenilin 1 by glycogen synthase kinase 3beta-mediated phosphorylation regulates the interaction with beta-catenin and its nuclear signaling. J Biol Chem 2007; 282: 14083-93.
90. Fluhrer R, Friedlein A, Haass C, Walter J. Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis. J Biol Chem 2004; 279: 1585-93.
91. Walter J, Schindzielorz A, Grunberg J, Haass C. Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis. Proc Natl Acad Sci USA 1999; 96: 1391-6.
92. Seeger M, Nordstedt C, Petanceska S, et al. Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc Natl Acad Sci USA 1997; 94: 5090-4.
93. Kuo LH, Hu MK, Hsu WM, et al. Tumor necrosis factor-alpha-elicited stimulation of gamma-secretase is mediated by c-Jun N-terminal kinase-dependent phosphorylation of presenilin and nicastrin. Mol Biol Cell 2008; 19: 4201-12.
94. van Leeuwen FW, de Kleijn DP, van den Hurk HH, et al. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science 1998; 279: 242-7.
95. Bergman A, Hansson EM, Pursglove SE, et al. Pen-2 is sequestered in the endoplasmic reticulum and subjected to ubiquitylation and proteasome-mediated degradation in the absence of presenilin. J Biol Chem 2004; 279: 16744-53.
96. He G, Qing H, Cai F, et al. Ubiquitin-proteasome pathway mediates degradation of APH-1. J Neurochem 2006; 99: 1403-12.
97. Fraser PE, Levesque G, Yu G, et al. Presenilin 1 is actively degraded by the 26S proteasome. Neurobiol Aging 1998; 19: S19-21.
98. Steiner H, Capell A, Pesold B, et al. Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J Biol Chem 1998; 273: 32322-31.
99. He G, Qing H, Tong Y, Cai F, Ishiura S, Song W. Degradation of nicastrin involves both proteasome and lysosome. J Neurochem 2007; 101: 982-92.
100. Mah AL, Perry G, Smith MA, Monteiro MJ. Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J Cell Biol 2000; 151: 847-62.
101. Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000; 1: 31-9.
102. Verdile G, Gandy SE, Martins RN. The role of presenilin and its interacting proteins in the biogenesis of Alzheimer's beta amyloid. Neurochem Res 2007; 32: 609-23.
103. Parks AL, Curtis D. Presenilin diversifies its portfolio. Trends Genet 2007; 23: 140-50.
104. Hass MR, Sato C, Kopan R, Zhao G. Presenilin: RIP and beyond. Semin Cell Dev Biol 2008; 20: 201-10.
105. Cordy JM, Hooper NM, Turner AJ. The involvement of lipid rafts in Alzheimer's disease. Mol Membr Biol 2006; 23: 111-22.
106. Cheng H, Vetrivel KS, Gong P, Meckler X, Parent A, Thinakaran G. Mechanisms of disease: new therapeutic strategies for Alzheimer's disease--targeting APP processing in lipid rafts. Nat Clin Pract Neurol 2007; 3: 374-82.
107. Marlow L, Cain M, Pappolla MA, Sambamurti K. Beta-secretase processing of the Alzheimer's amyloid protein precursor (APP). J Mol Neurosci 2003; 20: 233-9.
108. Vetrivel KS, Cheng H, Kim SH, et al. Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J Biol Chem 2005; 280: 25892-900.
109. Gupta-Rossi N, Six E, LeBail O, et al. Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J Cell Biol 2004; 166(1): 73-83.
110. Twomey C, Qian S, McCarthy JV. TRAF6 promotes ubiquitination and regulated intramembrane proteolysis of IL-1R1. Biochem Biophys Res Commun 2009; 381: 418-23.
111. Underwood CK, Reid K, May LM, Bartlett PF, Coulson EJ. Palmitoylation of the C-terminal fragment of p75(NTR) regulates death signaling and is required for subsequent cleavage by gamma-secretase. Mol Cell Neurosci 2008; 37: 346-58.
112. Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998; 393: 382-6.
113. Yamasaki A, Eimer S, Okochi M, et al. The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase. J Neurosci 2006; 26: 3821-8.
114. Kopan R, Ilagan MX. Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 2004; 5: 499-504.
115. Hebert SS, Serneels L, Tolia A, et al. Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes. EMBO Rep 2006; 7: 739-45.
116. Pardossi-Piquard R, Petit A, Kawarai T, et al. Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP. Neuron 2005; 46: 541-54.
117. Maetzel D, Denzel S, Mack B, et al. Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 2009; 11: 162-71.
118. Carpenter G, Red Brewer M. EpCAM: another surface-to-nucleus missile. Cancer Cell 2009; 15: 165-6.
119. Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 2006; 127: 185-97.
120. Jung KM, Tan S, Landman N, et al. Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor. J Biol Chem 2003; 278: 42161-9.
121. Wang L, Rahn JJ, Lun X, et al. Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor. PLoS Biol 2008; 6: e289.
122. Louvi A, Artavanis-Tsakonas S. Notch signalling in vertebrate neural development. Nat Rev Neurosci 2006; 7: 93-102.
123. Barten DM, Albright CF. Therapeutic strategies for Alzheimer's disease. Mol Neurobiol 2008; 37: 171-86.
124. Olson RE, Albright CF. Recent progress in the medicinal chemistry of gamma-secretase inhibitors. Curr Top Med Chem 2008; 8: 17-33.
125. Kukar TL, Ladd TB, Bann MA, et al. Substrate-targeting gamma-secretase modulators. Nature 2008; 453: 925-9.
126. Wolfe MS. gamma-Secretase modulators. Curr Alzheimer Res 2007; 4: 571-3.
127. Imbimbo BP. Alzheimer's disease: gamma-secretase inhibitors. Drug Discovery Today: Therapeutic Strategies 2008; 5: 169-75.
128. Imbimbo BP. Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem 2008; 8: 54-61.
129. Beel AJ, Sanders CR. Substrate specificity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci 2008; 65: 1311-34.
130. Siemers ER, Quinn JF, Kaye J, et al. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006; 66: 602-4.
131. Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 2007; 30: 317-25.
132. De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999; 398: 518-22.
133. Allman D, Aster JC, Pear WS. Notch signaling in hematopoiesis and early lymphocyte development. Immunol Rev 2002; 187: 75-86.
134. Glen Frick SR, Hong Wan, Stephen BF, et al. GSI-953, a potent and selective gamma-secretase inhibitor: Modulation of beta-amyloid peptides and plasma and cerebrospinal fluid pharmacokinetic/pharmacodynamic relationships in humans. Alzheimers Dement 2008; 4: T781.
135. Karen JC, Stacey LB, Jeffrey van D, et al. Efficacy of the novel gamma-secretase inhibitor, PF-3084014, in reducing Abeta in brain, CSF, and plasma in guinea pigs and Tg2576 mice. In; Alzheimers Dement 2008; p. T482-T83.
136. Sato T, Nyborg AC, Iwata N, et al. Signal peptide peptidase: biochemical properties and modulation by nonsteroidal antiinflammatory drugs. Biochemistry 2006; 45: 8649-56.
137. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414: 212-6.
138. Kukar T, Golde TE. Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage. Curr Top Med Chem 2008; 8: 47-53.
139. Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science 2004; 305: 1119-23.
140. Wolfe MS. Tau Mutations in Neurodegenerative Diseases. J Biol Chem 2009; 284: 6021-25.
141. Iben LG, Olson RE, Balanda LA, et al. Signal peptide peptidase and gamma-secretase share equivalent inhibitor binding pharmacology. J Biol Chem 2007; 282: 36829-36.
142. Golde TE, Michael S. Wolfe, Doron C. Greenbaum. Signal peptide peptidases: A family of intramembrane-cleaving proteases that cleave type 2 transmembrane proteins. Semin Cell Dev Biol 2009; 20: 225-30.
143. Lee HJ, Jung KM, Huang YZ, et al. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J Biol Chem 2002; 277: 6318-23.
144. McElroy B, Powell JC, McCarthy JV. The insulin-like growth factor 1 (IGF-1) receptor is a substrate for gamma-secretase-mediated intramembrane proteolysis. Biochem Biophys Res Commun 2007; 358: 1136-41.
145. Powell JC, Twomey C, Jain R, McCarthy JV. Association between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTR neurotrophin receptor. J Neurochem 2009; 108: 216-30.
146. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ. Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood 2007; 110: 278-86.
147. Grabher C, von Boehmer H, Look AT. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 2006; 6: 347-59.
148. Shih Ie M, Wang TL. Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 2007; 67: 1879-82.
149. Larsson O, Girnita A, Girnita L. Role of insulin-like growth factor 1 receptor signalling in cancer. Br J Cancer 2007; 96 Suppl: R2-6.
150. Johnston AL, Lun X, Rahn JJ, et al. The p75 neurotrophin receptor is a central regulator of glioma invasion. PLoS Biol 2007; 5: e212.
151. Went PT, Lugli A, Meier S, et al. Frequent EpCam protein expression in human carcinomas. Hum Pathol 2004; 35: 122-8.
152. Wang W, Zhao H, Zhang S, et al. Patterns of expression and function of the p75(NGFR) protein in pancreatic cancer cells and tumours. Eur J Surg Oncol 2008; 35: 826-32.
153. Das I, Craig C, Funahashi Y, et al. Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function. J Biol Chem 2004; 279: 30771-80.
154. Laura R, Andrew P, Jinyu Y, et al. The gamma secretase inhibitor MK-0752 acutely and significantly reduces CSF Abeta40 concentrations in humans. Alzheimers Dement 2006; 2: S79.
155. DeAngelo DJ, Stone RM, Silverman LB, et al. A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2006; 24: 6585.
156. Shirotani K, Takahashi K, Araki W, Maruyama K, Tabira T. Mutational analysis of intrinsic regions of presenilin 2 that determine its endoproteolytic cleavage and pathological function. J Biol Chem 2000; 275: 3681-6.
157. Fleisher AS, Raman R, Siemers ER, et al. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch Neurol 2008; 65: 1031-8.
158. Siemers E, Skinner M, Dean RA, et al. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005; 28: 126-32.
159. Steven JTC, Suzan A, Hua Z, et al. P2-302: GSI-953 is a potent APP-selective gamma-secretase inhibitor for the treatment of Alzheimer's disease. Alzheimers Dement 2008; 4: T461.