The structure and function of Alzheimer's gamma secretase enzyme complex

Critical Reviews in Clinical Laboratory Sciences

Volumn 46, Issue 5-6, 2009, Pages 282-301

  Krishnaswamy, Sudarsan ^a   Verdile, Giuseppe ^a,b,c   Groth, David ^a,c,d   Kanyenda, Limbikani ^a   Martins, Ralph N ^a,b,c  

^a EDITH COWAN UNIVERSITY   (Australia)

^b UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^c HOLLYWOOD PRIVATE HOSPITAL   (Australia)

^d CURTIN UNIVERSITY   (Australia)

Author keywords

Alzheimer's disease; Amyloid precursor protein; Anterior pharynx defective homolog 1; Beta amyloid; Gamma secretase; Nicastrin; Notch receptor; Presenilin enhnacer 2; Presenilins; Regulated intramembrane proteolysis

Indexed keywords

ACETYLCHOLINE; AMYLOID BETA PROTEIN; BLOCKING AGENT; BMS 299897; CHOLINESTERASE INHIBITOR; DONEPEZIL; FLURBIPROFEN; GALANTAMINE; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; IMATINIB; L 685458; MEMANTINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; N2 [2 (3,5 DIFLUOROPHENYL) 2 HYDROXYACETYL] N1 (6,7 DIHYDRO 5 METHYL 6 OXO 5H DIBENZ[B,D]AZEPIN 7 YL)ALANINAMIDE; NERVE CELL ADHESION MOLECULE; NEUROTRANSMITTER; NONSTEROID ANTIINFLAMMATORY AGENT; PLACEBO; PRESENILIN 1; PRESENILIN 2; RIVASTIGMINE; SEMAGACESTAT; STEROL REGULATORY ELEMENT BINDING PROTEIN; TARENFLURBIL; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; BRAIN HOMOGENATE; CLINICAL TRIAL; DRUG INHIBITION; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME MECHANISM; ENZYME STRUCTURE; GASTROINTESTINAL SYMPTOM; GENE MUTATION; HUMAN; NONHUMAN; PEPTIC ULCER; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN INTERACTION; REVIEW;

ALZHEIMER DISEASE; AMINO ACID SEQUENCE; AMYLOID BETA-PROTEIN; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; DISEASE MODELS, ANIMAL; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; MOLECULAR SEQUENCE DATA; PROTEIN CONFORMATION;

ANIMALIA;

EID: 71849111111     PISSN: 10408363     EISSN: 1549781X     Source Type: Journal    
DOI: 10.3109/10408360903335821     Document Type: Review

References (214)

1. Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martins RN. Te role of beta amyloid in Alzheimer's disease: still a cause of everything or the only one who got caught? Pharmacol Res 2004; 50: 397-409.
2. Reddy PH. Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease. J Neurochem 2006; 96: 1-13.
3. Verdile G, Groth D, Mathews PM, St George-Hyslop P, Fraser PE, Ramabhadran T V, Kwok JB, Schofeld PR, Carter T, Gandy S, Martins RN. Baculoviruses expressing the human familial Alzheimer's disease presenilin 1 mutation lacking exon 9 increase levels of an amyloid beta-like protein in Sf9 cells. Mol Psychiatry 2004; 9: 594-602.
4. Gandy S, Naslund J, Nordstedt C. Alzheimer's disease. Molecular consequences of presenilin-1 mutation. Nature 2001; 411: 654-6546.
5. Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y. Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch. J Biol Chem 2001; 276: 35235-35238.
6. Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, Condron MM, Teplow DB, Haass C. Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2001; 2: 835-841.
7. Yu C, Kim SH, Ikeuchi T, Xu H, Gasparini L, Wang R, Sisodia SS. Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma. Evidence for distinct mechanisms involved in gamma-secretase processing of the APP and Notch1 transmembrane domains. J Biol Chem 2001; 276: 43756-43760.
8. Weidemann A, Eggert S, Reinhard FB, Vogel M, Paliga K, Baier G, Masters CL, Beyreuther K, Evin G. A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 2002; 41: 2825-2835.
9. Raychaudhuri M, Mukhopadhyay D. AICD and its adap-tors-in search of new players. J Alzheimers Dis 2007; 11: 343-358.
10. Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998; 393: 382-386.
11. Zhao G, Mao G, Tan J, Dong Y, Cui MZ, Kim SH, Xu X. Identifcation of a new presenilin-dependent zeta-cleavage site within the transmembrane domain of amyloid precursor protein. J Biol Chem 2004; 279: 50647-50650.
12. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramem-brane cleavage by gamma-secretase. J Neurosci 2005; 25: 436-445.
13. Zhao G, Tan J, Mao G, Cui MZ, Xu X, Dong Y, Singh N, Sun L, Kim SH. Te same gamma-secretase accounts for the multiple intramembrane cleavages of APP. J Neurochem 2007; 100: 1234-1246.
14. Parks AL, Curtis D. Presenilin diversifes its portfolio. Trends Genet 2007; 23: 140-150.
15. 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: 6382-6387.
16. Yu G, Chen F, Levesque G, Nishimura M, Zhang DM, Levesque L, Rogaeva E, Xu D, Liang Y, Duthie M, St George-Hyslop PH, Fraser PE. Te presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J Biol Chem 1998; 273: 16470-16475.
17. Farmery MR, Tjernberg LO, Pursglove SE, Bergman A, Winblad B, Naslund J. Partial purifcation and characterization of gamma-secretase from post-mortem human brain. J Biol Chem 2003; 278: 24277-24284.
18. Edbauer D, Winkler E, Haass C, Steiner H. Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Proc Natl Acad Sci USA 2002; 99: 8666-8671.
19. Steiner H, Winkler E, Edbauer D, Prokop S, Basset G, Yamasaki A, Kostka M, Haass C. PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem 2002; 277: 39062-39065.
20. Li T, Ma G, Cai H, Price DL, Wong PC. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafcking of beta-amyloid precursor protein in mammals. J Neurosci 2003; 23: 3272-3277.
21. Nyabi O, Bentahir M, Horre K, Herreman A, Gottardi-Littell N, Van Broeckhoven C, Merchiers P, Spittaels K, Annaert W, De Strooper B. Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glyco-sylation but remain catalytically inactive in the absence of wild type Presenilin. J Biol Chem 2003; 278: 43430-43436.
22. Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, Shi XP, Yin KC, Shafer JA, Gardell SJ. Presenilin 1 is linked with gamma-secretase activity in the detergent sol-ubilized state. Proc Natl Acad Sci USA 2000; 97: 6138-6143.
23. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 2002; 3: 85-97.
24. Lee SF, Shah S, Li H, Yu C, Han W, Yu G. Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem 2002; 277: 45013-45019.
25. Gu Y, Chen F, Sanjo N, Kawarai T, Hasegawa H, Duthie M, Li W, Ruan X, Luthra A, Mount HT, Tandon A, Fraser PE, St George-Hyslop P. APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin-nicastrin complexes. J Biol Chem 2003; 278: 7374-7380.
26. Hu Y, Fortini ME. Diferent cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcom-plex. J Cell Biol 2003; 161: 685-690.
27. Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Tinakaran G, Kim TW, Yu G, Xu H. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem 2003; 278: 7850-7854.
28. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Tinakaran G, Iwatsubo T. Te role of preseni-lin cofactors in the gamma-secretase complex. Nature 2003; 422: 438-441.
29. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol 2003; 5: 486-488.
30. Hayashi I, Urano Y, Fukuda R, Isoo N, Kodama T, Hamakubo T, Tomita T, Iwatsubo T. Selective reconstitution and recovery of functional gamma-secretase complex on budded baculo-virus particles. J Biol Chem 2004; 279: 38040-38046.
31. Zhang L, Lee J, Song L, Sun X, Shen J, Terracina G, Parker EM. Characterization of the reconstituted gamma-secretase complex from Sf9 cells co-expressing presenilin 1, nicastrin [correction of nacastrin], aph-1a, and pen-2. Biochemistry 2005; 44: 4450-4457.
32. Brunkan AL, Martinez M, Wang J, Walker ES, Beher D, Shearman MS, Goate AM. Two domains within the frst putative transmembrane domain of presenilin 1 diferen-tially infuence presenilinase and gamma-secretase activity. J Neurochem 2005; 94: 1315-1328.
33. Lazarov, V. K., P. C. Fraering, et al. (2006). "Electron microscopic structure of purifed, active gamma-secretase reveals an aqueous intramembrane chamber and two pores." Proc Natl Acad Sci U S A 103(18): 6889-6894.
34. Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, Kopan R, Kodama T, Hamakubo T, Iwastubo T, Tomita T, Sato C. Tree-dimensional structure of the [gamma]-secretase complex. Biochemical and Biophysical Research Communications 2006; 343: 525-534.
35. Wang Y, Zhang Y, Ha Y. Crystal structure of a rhomboid family intramembrane protease. Nature 2006; 444: 179-180.
36. Kim AC, Oliver DC, Paetzel M. Crystal structure of a bacterial signal peptide peptidase. J Mol Biol 2008; 376: 352-366.
37. Stahlberg H, Fotiadis D, Scheuring S, Remigy H, Braun T, Mitsuoka K, Fujiyoshi Y, Engel A. Two-dimensional crystals: a powerful approach to assess structure, function and dynamics of membrane proteins. FEBS Lett 2001; 504: 166-172.
38. Capell A, Beher D, Prokop S, Steiner H, Kaether C, Shearman MS, Haass C. Gamma-secretase complex assembly within the early secretory pathway. J Biol Chem 2005; 280: 6471-6478.
39. Kim SH, Yin YI, Li YM, Sisodia SS. Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway. J Biol Chem 2004; 279: 48615-48619.
40. LaVoie MJ, Fraering PC, Ostaszewski BL, Ye W, Kimberly WT, Wolfe MS, Selkoe DJ. Assembly of the gamma-secretase complex involves early formation of an intermediate sub-complex of Aph-1 and nicastrin. J Biol Chem 2003; 278: 37213-37222.
41. Fortna RR, Crystal AS, Morais VA, Pijak DS, Lee VM, Doms RW. Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the gamma-secretase complex. J Biol Chem 2004; 279: 3685-3693.
42. Lee SF, Shah S, Yu C, Wigley WC, Li H, Lim M, Pedersen K, Han W, Tomas P, Lundkvist J, Hao YH, Yu G. A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J Biol Chem 2004; 279: 4144-4152.
43. Niimura M, Isoo N, Takasugi N, Tsuruoka M, Ui-Tei K, Saigo K, Morohashi Y, Tomita T, Iwatsubo T. Aph-1 contributes to the stabilization and trafcking of the gamma-secretase complex through mechanisms involving intermolecular and intramolecular interactions. J Biol Chem 2005; 280: 12967-12975.
44. Shirotani K, Edbauer D, Kostka M, Steiner H, Haass C. Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identifcation of nicastrin mutants that selectively interact with APH-1. J Neurochem 2004; 89: 1520-1527.
45. Zhang YW, Luo WJ, Wang H, Lin P, Vetrivel KS, Liao F, Li F, Wong PC, Farquhar MG, Tinakaran G, Xu H. Nicastrin is critical for stability and trafcking but not association of other presenilin/gamma-secretase components. J Biol Chem 2005; 280: 17020-17026.
46. Shah S, Lee S-F, Tabuchi K, Hao Y-H, Yu C, LaPlant Q, Ball H, Dann Iii CE, Südhof T, Yu G. Nicastrin Functions as a [gamma]-Secretase-Substrate Receptor. Cell 2005; 122: 435-447.
47. Hasegawa H, Sanjo N, Chen F, Gu YJ, Shier C, Petit A, Kawarai T, Katayama T, Schmidt SD, Mathews PM, Schmitt-Ulms G, Fraser PE, St George-Hyslop P. Both the sequence and length of the C terminus of PEN-2 are critical for inter-molecular interactions and function of presenilin complexes. J Biol Chem 2004; 279: 46455-46463.
48. 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: 41967-41975.
49. Kim SH, Sisodia SS. Evidence that the "NF" motif in trans-membrane domain 4 of presenilin 1 is critical for binding with PEN-2. J Biol Chem 2005; 280: 41953-41966.
50. Borchelt DR, Tinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 1996; 17: 1005-1013.
51. Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, Yamaguchi H, Ruiz A, Martinez A, Madrigal L, Hincapie L, Arango JC, Anthony DC, Koo EH, Goate AM, Selkoe DJ. Te E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med 1996; 2: 1146-1150.
52. Xia W, Zhang J, Kholodenko D, Citron M, Podlisny MB, Teplow DB, Haass C, Seubert P, Koo EH, Selkoe DJ. Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins. J Biol Chem 1997; 272: 7977-7982.
53. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Defciency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391: 387-390.
54. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly W T, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999; 398: 513-517.
55. Steiner H, Duf K, Capell A, Romig H, Grim MG, Lincoln S, Hardy J, Yu X, Picciano M, Fechteler K, Citron M, Kopan R, Pesold B, Keck S, Baader M, Tomita T, Iwatsubo T, Baumeister R, Haass C. A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and Notch signaling. J Biol Chem 1999; 274: 28669-28673.
56. Esler WP, Kimberly W T, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS. Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol 2000; 2: 428-434.
57. Seifert D, Mitchell T, Stern AM, Roach A, Zhan Y, Grzanna R. Positive-negative epitope-tagging of beta amyloid precursor protein to identify inhibitors of A beta processing. Brain Res Mol Brain Res 2000; 84: 115-126.
58. Verdile G, Gandy SE, Martins RN. Te role of presenilin and its interacting proteins in the biogenesis of Alzheimer's beta amyloid. Neurochem Res 2007; 32: 609-623.
59. Tinakaran G, Teplow DB, Siman R, Greenberg B, Sisodia SS. Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the "beta-secretase" site occurs in the golgi apparatus. J Biol Chem 1996; 271: 9390-9397.
60. Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, Diehl T, Levesque G, Fraser P, Haass C, Koo EH, Seubert P, St George-Hyslop P, Teplow DB, Selkoe DJ. Presenilin proteins undergo heterogeneous endoproteoly-sis between Tr291 and Ala299 and occur as stable N-and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis 1997; 3: 325-337.
61. Levitan D, Lee J, Song L, Manning R, Wong G, Parker E, Zhang L. PS1 N-and C-terminal fragments form a complex that functions in APP processing and Notch signaling. Proc Natl Acad Sci USA 2001; 98: 12186-12190.
62. Laudon H, Mathews PM, Karlstrom H, Bergman A, Farmery MR, Nixon RA, Winblad B, Gandy SE, Lendahl U, Lundkvist J, Naslund J. Co-expressed presenilin 1 NTF and CTF form functional gamma-secretase complexes in cells devoid of full-length protein. J Neurochem 2004; 89: 44-53.
63. Capell A, Grunberg J, Pesold B, Diehlmann A, Citron M, Nixon R, Beyreuther K, Selkoe DJ, Haass C. Te proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J Biol Chem 1998; 273: 3205-3211.
64. Seeger M, Nordstedt C, Petanceska S, Kovacs DM, Gouras GK, Hahne S, Fraser P, Levesque L, Czernik AJ, George-Hyslop PS, Sisodia SS, Tinakaran G, Tanzi RE, Greengard P, Gandy S. Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc Natl Acad Sci USA 1997; 94: 5090-5094.
65. Steiner H, Capell A, Pesold B, Citron M, Kloetzel PM, Selkoe DJ, Romig H, Mendla K, Haass C. Expression of Alzheimer's disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J Biol Chem 1998; 273: 32322-32331. (Pubitemid 29177180)
66. Beher D, Elle C, Underwood J, Davis JB, Ward R, Karran E, Masters CL, Beyreuther K, Multhaup G. Proteolytic fragments of Alzheimer's disease-associated presenilin 1 are present in synaptic organelles and growth cone membranes of rat brain. J Neurochem 1999; 72: 1564-1573.
67. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P. Nicastrin modulates presenilin-mediated Notch/glp-1 signal transduction and betaAPP processing. Nature 2000; 407: 48-54.
68. Cervantes S, Gonzalez-Duarte R, Marfany G. Homodimerization of presenilin N-terminal fragments is afected by mutations linked to Alzheimer's disease. FEBS Lett 2001; 505: 81-86.
69. Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Goate A, Wolfe MS, Shearman M, Kopan R. A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci USA2003; 100: 13075-13080.
70. Xia W, Wolfe MS. Intramembrane proteolysis by prese-nilin and presenilin-like proteases. J Cell Sci 2003; 116: 2839-2844.
71. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. Identifcation of signal peptide peptidase, a presenilin-type aspartic protease. Science 2002; 296: 2215-2218.
72. Nyborg AC, Kornilova AY, Jansen K, Ladd TB, Wolfe MS, Golde TE. Signal peptide peptidase forms a homodimer that is labeled by an active site-directed gamma-secretase inhibitor. J Biol Chem 2004; 279: 15153-15160.
73. Friedmann E, Lemberg MK, Weihofen A, Dev KK, Dengler U, Rovelli G, Martoglio B. Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins. J Biol Chem 2004; 279: 50790-50798.
74. Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. Identifcation of a novel family of presenilin homologues. Hum Mol Genet 2002; 11: 1037-1044.
75. Sato T, Nyborg AC, Iwata N, Diehl TS, Saido TC, Golde TE, Wolfe MS. Signal peptide peptidase: biochemical properties and modulation by nonsteroidal antiinfammatory drugs. Biochemistry 2006; 45: 8649-8656.
76. Lemberg MK, Martoglio B. Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol Cell 2002; 10: 735-744.
77. Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science 2004; 305: 1119-1123.
78. Fluhrer R, Fukumori A, Martin L, Grammer G, Haug-Kroper M, Klier B, Winkler E, Kremmer E, Condron MM, Teplow DB, Steiner H, Haass C. Intramembrane proteoly-sis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. J Biol Chem 2008; 283: 30121-30128.
79. Leuchtenberger S, Beher D, Weggen S. Selective modulation of Abeta42 production in Alzheimer's disease: non-steroidal anti-infammatory drugs and beyond. Curr Pharm Des 2006; 12: 4337-4355.
80. Berezovska O, Ramdya P, Skoch J, Wolfe MS, Bacskai BJ, Hyman BT. Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin 1-gamma-secretase complex in cells demonstrated by fuo-rescence lifetime imaging. J Neurosci 2003; 23: 4560-4566.
81. Spasic D, Annaert W. Building gamma-secretase: the bits and pieces. J Cell Sci 2008; 121: 413-420.
82. Hansson EM, Stromberg K, Bergstedt S, Yu G, Naslund J, Lundkvist J, Lendahl U. Aph-1 interacts at the cell surface with proteins in the active gamma-secretase complex and membrane-tethered Notch. J Neurochem 2005; 92: 1010-1020.
83. Urban S, Lee JR, Freeman M. Drosophila rhomboid-1 defnes a family of putative intramembrane serine proteases. Cell 2001; 107: 173-182.
84. Prokop S, Haass C, Steiner H. Length and overall sequence of the PEN-2 C-terminal domain determines its function in the stabilization of presenilin fragments. J Neurochem 2005; 94: 57-62.
85. Blum R, Feick P, Puype M, Vandekerckhove J, Klengel R, Nastainczyk W, Schulz I. Tmp21 and p24A, two type I proteins enriched in pancreatic microsomal membranes, are members of a protein family involved in vesicular trafck-ing. J Biol Chem 1996; 271: 17183-17189.
86. Barr FA, Preisinger C, Kopajtich R, Korner R. Golgi matrix proteins interact with p24 cargo receptors and aid their ef-cient retention in the Golgi apparatus. J Cell Biol 2001; 155: 885-891.
87. Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P. TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 2006; 440: 1208-1212.
88. Zhou S, Zhou H, Walian PJ, Jap BK. CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production. Proc Natl Acad Sci USA 2005; 102: 7499-7504.
89. Vetrivel KS, Zhang X, Meckler X, Cheng H, Lee S, Gong P, Lopes KO, Chen Y, Iwata N, Yin KJ, Lee JM, Parent AT, Saido TC, Li YM, Sisodia SS, Tinakaran G. Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta. J Biol Chem 2008; 283: 19489-19498.
90. Winkler E, Hobson S, Fukumori A, Dumpelfeld B, Luebbers T, Baumann K, Haass C, Hopf C, Steiner H. Purifcation, pharmacological modulation, and biochemical characterization of interactors of endogenous human gamma-secretase. Biochemistry 2009; 48: 1183-1197.
91. Schellenberg GD, Kamino K, Bryant EM, Moore D, Bird TD. Genetic heterogeneity, Down syndrome, and Alzheimer disease. Prog Clin Biol Res 1992; 379: 215-226.
92. St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M, Foncin JF, Montesi M, Bruni A, Sorbi S et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat Genet 1992; 2: 330-334.
93. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995; 375: 754-760.
94. Levy-Lahad E, Lahad A, Wijsman EM, Bird TD, Schellenberg GD. Apolipoprotein E genotypes and age of onset in early-onset familial Alzheimer's disease. Ann Neurol 1995; 38: 678-680.
95. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T et al. 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 1995; 376: 775-778.
96. Lao JI, Beyer K, Fernandez-Novoa L, Cacabelos R. A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease. Neurogenetics 1998; 1: 293-296.
97. Zekanowski C, Styczynska M, Peplonska B, Gabryelewicz T, Religa D, Ilkowski J, Kijanowska-Haladyna B, Kotapka-Minc S, Mikkelsen S, Pfefer A, Barczak A, Luczywek E, Wasiak B, Chodakowska-Zebrowska M, Gustaw K, Laczkowski J, Sobow T, Kuznicki J, Barcikowska M. Mutations in preseni-lin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol 2003; 184: 991-996.
98. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 1996; 2: 864-870.
99. Duf K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 1996; 383: 710-713.
100. Ishii K, Ii K, Hasegawa T, Shoji S, Doi A, Mori H. Increased A beta 42(43)-plaque deposition in early-onset familial Alzheimer's disease brains with the deletion of exon 9 and the missense point mutation (H163R) in the PS-1 gene. Neurosci Lett 1997; 228: 17-20.
101. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and trans-genic mice. Nat Med 1997; 3: 67-72.
102. Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 diferent presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett 1999; 265: 61-63.
103. Wolfe MS. When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 2007; 8: 136-140.
104. De Strooper B. Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of preseni-lin mutations in Alzheimer disease. EMBO Rep 2007; 8: 141-146.
105. Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grunberg J, Haass C. Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1997; 1: 149-159.
106. Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B. Presenilin clinical mutations can afect gamma-secretase activity by diferent mechanisms. J Neurochem 2006; 96: 732-1142.
107. Kumar-Singh S, Teuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, Cruts M, Dermaut B, Wang R, Van Broeckhoven C. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat 2006; 27: 686-695.
108. Bartus RT, Dean RL 3rd, Beer B, Lippa AS. Te cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217: 408-414.
109. Kidd PM. Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev 2008; 13: 85-115.
110. Alberts B, Johnson A, Lewis J et al. Molecular Biology of the Cell 4 ed. 2002.
111. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Booker L, Oremus M. Efectiveness of cholineste-rase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148: 379-397.
112. Winblad B, Jones RW, Wirth Y, Stofer A, Mobius HJ. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007; 24: 20-27.
113. Beel AJ, Sanders CR. Substrate specifcity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci 2008; 65: 1311-1334.
114. Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Proteomic profl-ing of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol 2008; 6: e257.
115. Wakabayashi T, De Strooper B. Presenilins: members of the gamma-secretase quartets, but part-time soloists too. Physiology (Bethesda) 2008; 23: 194-204.
116. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK. A CBP binding transcriptional repres-sor produced by the PS1/[epsilon]-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003; 114: 635-645.
117. Okamoto I, Kawano Y, Murakami D, Sasayama T, Araki N, Miki T, Wong AJ, Saya H. Proteolytic release of CD44 intra-cellular domain and its role in the CD44 signaling pathway. J Cell Biol 2001; 155: 755-762.
118. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127-137.
119. Ni CY, Yuan H, Carpenter G. Role of the ErbB-4 carboxyl terminus in gamma-secretase cleavage. J Biol Chem 2003; 278: 4561-4565.
120. Lee HJ, Jung KM, Huang YZ, Bennett LB, Lee JS, Mei L, Kim TW. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J Biol Chem 2002; 277: 6318-6323.
121. Ni CY, Murphy MP, Golde TE, Carpenter G. gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyro-sine kinase. Science 2001; 294: 2179-2181.
122. Fortini ME. Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol 2002; 3: 673-684.
123. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999; 284: 770-776.
124. Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC. Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 2004; 24: 9265-9273.
125. Tousseyn T, Tathiah A, Jorissen E, Raemaekers T, Konietzko U, Reiss K, Maes E, Snellinx A, Serneels L, Nyabi O, Annaert W, Saftig P, Hartmann D, De Strooper B. ADAM10, the rate-limiting protease of regulated intramem-brane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the gamma-secretase. J Biol Chem 2009; 284: 11738-11747.
126. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracel-lular domain. Nature 1999; 398: 518-522.
127. Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, Kopan R. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 2000; 5: 197-206.
128. Okochi M, Fukumori A, Jiang J, Itoh N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M. Secretion of the Notch-1 Abeta-like peptide during Notch signaling. J Biol Chem 2006; 281: 7890-7898.
129. Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 2002; 21: 5408-5416.
130. Kimberly WT, Esler WP, Ye W, Ostaszewski BL, Gao J, Diehl T, Selkoe DJ, Wolfe MS. Notch and the amyloid precursor protein are cleaved by similar gamma-secretase(s). Biochemistry 2003; 42: 137-144.
131. Berezovska O, Jack C, Deng A, Gastineau N, Rebeck GW, Hyman BT. Notch1 and amyloid precursor protein are competitive substrates for presenilin1-dependent gamma-secretase cleavage. J Biol Chem 2001; 276: 30018-30023.
132. Lleo A, Berezovska O, Ramdya P, Fukumoto H, Raju S, Shah T, Hyman BT. Notch1 competes with the amyloid precursor protein for gamma-secretase and down-regulates preseni-lin-1 gene expression. J Biol Chem 2003; 278: 47370-47375.
133. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-defcient mice. Cell 1997; 89: 629-639.
134. Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F, De Strooper B. Presenilin 2 defciency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 defciency. Proc Natl Acad Sci USA 1999; 96: 11872-11877.
135. Rozmahel R, Huang J, Chen F, Liang Y, Nguyen V, Ikeda M, Levesque G, Yu G, Nishimura M, Mathews P, Schmidt SD, Mercken M, Bergeron C, Westaway D, St George-Hyslop P, Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP. Neurobiol Aging 2002; 23: 187-194.
136. Lai MT, Chen E, Crouthamel MC, DiMuzio-Mower J, Xu M, Huang Q, Price E, Register RB, Shi XP, Donoviel DB, Bernstein A, Hazuda D, Gardell SJ, Li YM. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem 2003; 278: 22475-22481.
137. Mastrangelo P, Mathews PM, Chishti MA, Schmidt SD, Gu Y, Yang J, Mazzella MJ, Coomaraswamy J, Horne P, Strome B, Pelly H, Levesque G, Ebeling C, Jiang Y, Nixon RA, Rozmahel R, Fraser PE, St George-Hyslop P, Carlson GA, Westaway D. Dissociated phenotypes in presenilin trans-genic mice defne functionally
138. Placanica L, Tarassishin L, Yang G, Peethumnongsin E, Kim SH, Zheng H, Sisodia SS, Li YM. Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes. J Biol Chem 2009; 284: 2967-2977.
139. 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: 192-198.
140. Serneels L, Dejaegere T, Craessaerts K, Horre K, Jorissen E, Tousseyn T, Hebert S, Coolen M, Martens G, Zwijsen A, Annaert W, Hartmann D, De Strooper B. Diferential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc Natl Acad Sci USA 2005; 102: 1719-1724.
141. Dejaegere T, Serneels L, Schafer MK, Van Biervliet J, Horre K, Depboylu C, Alvarez-Fischer D, Herreman A, Willem M, Haass C, Hoglinger GU, D'Hooge R, De Strooper B. Defciency 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: 9775-9780.
142. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ. Photoactivated gamma-secretase inhibitors directed to the active site covalently label prese-nilin 1. Nature 2000; 405: 689-694.
143. Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, Nadin A, Smith AL, Stevenson G, Castro JL. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 2000; 39: 8698-8704.
144. Martys-Zage JL, Kim SH, Berechid B, Bingham SJ, Chu S, Sklar J, Nye J, Sisodia SS. Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of Notch 1. J Mol Neurosci 2000; 15: 189-204.
145. Lewis HD, Perez Revuelta BI, Nadin A, Neduvelil JG, Harrison T, Pollack SJ, Shearman MS. Catalytic site-directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages. Biochemistry 2003; 42: 7580-7586.
146. Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, Edbauer D, Walter J, Steiner H, Haass C. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J Biol Chem 2002; 277: 44754-44759.
147. Haas IG, Frank M, Veron N, Kemler R. Presenilin-dependent processing and nuclear function of gamma-protocadherins. J Biol Chem 2005; 280: 9313-9319.
148. Evin G, Sharples RA, Weidemann A, Reinhard FB, Carbone V, Culvenor JG, Holsinger RM, Sernee MF, Beyreuther K, Masters CL. Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer's disease. Biochemistry 2001; 40: 8359-8368.
149. Xiong K, Clough RW, Luo XG, Struble RG, Li YM, Yan XX. [3H]-L-685,458 as a radiotracer that maps gamma-secretase complex in the rat brain: relevance to Abeta genesis and presence of active presenilin-1 components. Brain Res 2007; 1157: 81-91.
150. Yao J, Duan L, Fan M, Wu X. Gamma-secretase inhibitors exerts antitumor activity via down-regulation of Notch and nuclear factor kappa B in human tongue carcinoma cells. Oral Dis 2007; 13: 555-563.
151. De Keersmaecker K. ABL1 fusions in T-cell acute lymphoblas-tic leukemia. Verh K Acad Geneeskd Belg 2008; 70: 245-255.
152. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL, Kholodenko D, Knops JE, Latimer LH, Lee M, Liao Z, Lieberburg IM, Motter RN, Mutter LC, Nietz J, Quinn KP, Sacchi KL, Seubert PA, Shopp GM, Torsett ED, Tung JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN, Britton TC, Clemens JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson KS, Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Audia JE. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001; 76: 173-181.
153. Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B, Merchant KM. Te gamma-secretase inhibitor N-[N-(3,5-difuorophenacetyl)-L-alanyl]-S- phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fuid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ter 2003; 305: 864-871.
154. Best JD, Jay MT, Otu F, Ma J, Nadin A, Ellis S, Lewis HD, Pattison C, Reilly M, Harrison T, Shearman MS, Williamson TL, Atack JR. Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebro-spinal fuid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difuorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6, 7-d ihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]. J Pharmacol Exp Ter 2005; 313: 902-908.
155. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, May PC. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gam-ma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005; 28: 126-132.
156. Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC. Efects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006; 66: 602-604.
157. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 2003; 278: 46107-46116.
158. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid pep-tide production and alters lymphopoiesis and intestinal cell diferentiation. J Biol Chem 2004; 279: 12876-12882.
159. Green RC, Schneider LS, Hendrix SB, Zavitz KH, Swabb E. Safety and efcacy of tarenfurbil in subjects with mild Alzheimer's disease: results from an 18-month multi-center phase 3 trial Alzheimer's & Dementia. J Alzheimer's Assoc 2008; 4: T165.
160. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Efcacy and safety of tarenfurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol 2008; 7: 483-493.
161. Britschgi M, Wyss-Coray T. Immune cells may fend of Alzheimer disease. Nat Med 2007; 13: 408-409.
162. Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci USA 2003; 100: 12444-12449.
163. Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J Biol Chem 2005; 280: 41987-41996.
164. Wolfe MS. Gamma-secretase inhibition and modulation for Alzheimer's disease. Curr Alzheimer Res 2008; 5: 158-164.
165. Vassar R, Citron M. Abeta-generating enzymes: recent advances in beta-and gamma-secretase research. Neuron 2000; 27: 419-422.
166. Ho A, Sudhof TC. Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci USA 2004; 101: 2548-2553.
167. Araki Y, Miyagi N, Kato N, Yoshida T, Wada S, Nishimura M, Komano H, Yamamoto T, De Strooper B, Yamamoto K, Suzuki T. Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation. J Biol Chem 2004; 279: 24343-24354.
168. Walsh DM, Fadeeva JV, LaVoie MJ, Paliga K, Eggert S, Kimberly W T, Wasco W, Selkoe DJ. gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins. Biochemistry 2003; 42: 6664-6673.
169. Eggert S, Paliga K, Soba P, Evin G, Masters CL, Weidemann A, Beyreuther K. Te proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation. J Biol Chem 2004; 279: 18146-18156.
170. Endres K, Postina R, Schroeder A, Mueller U, Fahrenholz F. Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin- metalloproteinases. FEBS J 2005; 272: 5808-5820.
171. Hoe HS, Rebeck GW. Regulation of ApoE receptor prote-olysis by ligand binding. Brain Res Mol Brain Res 2005; 137: 31-39.
172. May P, Bock HH, Nimpf J, Herz J. Diferential glycosylation regulates processing of lipoprotein receptors by gamma-secretase. J Biol Chem 2003; 278: 37386-37392.
173. Brown MS, Goldstein JL. Te SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997; 89: 331-340.
174. Tomita T, Tanaka S, Morohashi Y, Iwatsubo T. Presenilin-dependent intramembrane cleavage of ephrin-B1. Mol Neurodegener 2006; 1: 2.
175. Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G, Robakis NK. Metalloproteinase/presenilin1 processing of ephrinB regulates EphB-induced Src phos-phorylation and signaling. EMBO J 2006; 25: 1242-1252.
176. Litterst C, Georgakopoulos A, Shioi J, Ghersi E, Wisniewski T, Wang R, Ludwig A, Robakis NK. Ligand binding and calcium infux induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. J Biol Chem 2007; 282: 16155-16163.
177. Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 2002; 21: 1948-1956.
178. Uemura K, Kihara T, Kuzuya A, Okawa K, Nishimoto T, Ninomiya H, Sugimoto H, Kinoshita A, Shimohama S. Characterization of sequential N-cadherin cleavage by ADAM10 and PS1. Neurosci Lett 2006; 402: 278-283.
179. Andersson CX, Fernandez-Rodriguez J, Laos S, Baeckstrom D, Haass C, Hansson GC. Shedding and gamma-secretase-mediated intramembrane proteolysis of the mucin-type molecule CD43. Biochem J 2005; 387: 377-384.
180. Murakami D, Okamoto I, Nagano O, Kawano Y, Tomita T, Iwatsubo T, De Strooper B, Yumoto E, Saya H. Presenilin-dependent gamma-secretase activity mediates the intramembranous cleavage of CD44. Oncogene 2003; 22: 1511-1516.
181. Schulte A, Schulz B, Andrzejewski MG, Hundhausen C, Mletzko S, Achilles J, Reiss K, Paliga K, Weber C, John SR, Ludwig A. Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha-and gam-ma-secretases. Biochem Biophys Res Commun 2007; 358: 233-240.
182. Shimizu K, Chiba S, Hosoya N, Kumano K, Saito T, Kurokawa M, Kanda Y, Hamada Y, Hirai H. Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2. Mol Cell Biol 2000; 20: 6913-7622.
183. Saxena MT, Schroeter EH, Mumm JS, Kopan R. Murine Notch homologs (N1-4) undergo presenilin-dependent pro-teolysis. J Biol Chem 2001; 276: 40268-40273.
184. Mizutani T, Taniguchi Y, Aoki T, Hashimoto N, Honjo T. Conservation of the biochemical mechanisms of signal transduction among mammalian Notch family members. Proc Natl Acad Sci USA 2001; 98: 9026-9031.
185. Wilhelmsen K, van der Geer P. Phorbol 12-myristate 13--acetate-induced release of the colony-stimulating factor 1 receptor cytoplasmic domain into the cytosol involves two separate cleavage events. Mol Cell Biol 2004; 24: 454-464.
186. Taniguchi Y, Kim SH, Sisodia SS. Presenilin-dependent "gamma-secretase" processing of deleted in colorectal cancer (DCC). J Biol Chem 2003; 278: 30425-30428.
187. Kim DY, Ingano LA, Kovacs DM. Nectin-1alpha, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/gamma-secretase-like cleavage. J Biol Chem 2002; 277: 49976-49981.
188. Gowrishankar K, Zeidler MG, Vincenz C. Release of a membrane-bound death domain by gamma-secretase processing of the p75NTR homolog NRADD. J Cell Sci 2004; 117: 4099-4111.
189. Meyer EL, Strutz N, Gahring LC, Rogers SW. Glutamate receptor subunit 3 is modifed by site-specifc limited pro-teolysis including cleavage by gamma-secretase. J Biol Chem 2003; 278: 23786-23796.
190. LaVoie MJ, Selkoe DJ. Te Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and preseni-lin/gamma-secretase and release signaling fragments. J Biol Chem 2003; 278: 34427-34437.
191. Ikeuchi T, Sisodia SS. Te Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage. J Biol Chem 2003; 278: 7751-7754.
192. von Arnim CA, Kinoshita A, Peltan ID, Tangredi MM, Herl L, Lee BM, Spoelgen R, Hshieh TT, Ranganathan S, Battey FD, Liu CX, Bacskai BJ, Sever S, Irizarry MC, Strickland DK,. Hyman BT. Te low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem 2005; 280: 17777-17785.
193. Zou Z, Chung B, Nguyen T, Mentone S, Tomson B, Biemesderfer D. Linking receptor-mediated endocytosis and cell signaling: evidence for regulated intramembrane proteolysis of megalin in proximal tubule. J Biol Chem 2004; 279: 34302-34310.
194. Mi K, Johnson GV. Regulated proteolytic processing of LRP6 results in release of its intracellular domain. J Neurochem 2007; 101: 517-529.
195. Kuhn PH, Marjaux E, Imhof A, De Strooper B, Haass C, Lichtenthaler SF. Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase. J Biol Chem 2007; 282: 11982-11995.
196. Urra S, Escudero CA, Ramos P, Lisbona F, Allende E, Covarrubias P, Parraguez JI, Zampieri N, Chao MV, Annaert W, Bronfman FC. TrkA receptor activation by nerve growth factor induces shedding of the p75 neurotrophin receptor followed by endosomal gamma-secretase-mediated release of the p75 intracellular domain. J Biol Chem 2007; 282: 7606-7615.
197. Cowan JW, Wang X, Guan R, He K, Jiang J, Baumann G, Black RA, Wolfe MS, Frank SJ. Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage. J Biol Chem 2005; 280: 19331-19342.
198. Nyborg AC, Ladd TB, Zwizinski CW, Lah JJ, Golde TE. Sortilin, SorCS1b, and SorLA Vps10p sorting receptors are novel gam-ma-secretase substrates. Mol Neurodegener 2006; 1: 3.
199. Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC. Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci 2000; 113(Pt 24): 4475-4485.
200. Wang R, Tang P, Wang P, Boissy RE, Zheng H. Regulation of tyrosinase trafcking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation. Proc Natl Acad Sci USA 2006; 103: 353-358.
201. Schulz JG, Annaert W, Vandekerckhove J, Zimmermann P, De Strooper B, David G. Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase- dependent and modulates cytosolic signaling. J Biol Chem 2003; 278: 48651-48657.
202. Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, De Strooper B, Saftig P, Nukina N. beta subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. J Biol Chem 2005; 280: 23009-23017.
203. Hiesberger T, Gourley E, Erickson A, Koulen P, Ward CJ, Masyuk TV, Larusso NF, Harris PC, Igarashi P. Proteolytic. cleavage and nuclear translocation of fbrocystin is regulated by intracellular Ca2+ and activation of protein kinase C. J Biol Chem 2006; 281: 34357-34364.
204. Haapasalo A, Kim DY, Carey BW, Turunen MK, Pettingell WH, Kovacs DM. Presenilin/gamma-secretase-mediated cleavage regulates association of leukocyte-common antigen-related (LAR) receptor tyrosine phosphatase with beta-catenin. J Biol Chem 2007; 282: 9063-9072.
205. Carey BW, Kim DY, Kovacs DM. Presenilin/gamma-secretase and alpha-secretase-like peptidases cleave human MHC Class I proteins. Biochem J 2007; 401: 121-127.
206. Kasuga K, Kaneko H, Nishizawa M, Onodera O, Ikeuchi T. Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase. Biochem Biophys Res Commun 2007; 360: 90-96.
207. Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D, Altevogt P, Saftig P, Reiss K. L1 is sequentially processed by two diferently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol 2005; 25: 9040-9053.
208. Bonn S, Seeburg PH, Schwarz MK. Combinatorial expression of alpha-and gamma-protocadherins alters their presenilin-dependent processing. Mol Cell Biol 2007; 27: 4121-4132.
209. Anders L, Mertins P, Lammich S, Murgia M, Hartmann D, Saftig P, Haass C, Ullrich A. Furin-, ADAM 10-, and gamma-secretase-mediated cleavage of a receptor tyrosine phos-phatase and regulation of beta-catenin's transcriptional activity. Mol Cell Biol 2006; 26: 3917-3934.
210. Cai J, Jiang WG, Grant MB, Boulton M. Pigment epithelium-derived factor inhibits angiogenesis via regulated intracellu-lar proteolysis of vascular endothelial growth factor receptor 1. J Biol Chem 2006; 281: 3604-3613.
211. Dyczynska E, Sun D, Yi H, Sehara-Fujisawa A, Blobel CP, Zolkiewska A. Proteolytic processing of delta-like 1 by ADAM proteases. J Biol Chem 2007; 282: 436-444.
212. McElroy B, Powell JC, McCarthy JV. Te insulin-like growth factor 1 (IGF-1) receptor is a substrate for gamma-secretase-mediated intramembrane proteolysis. Biochem Biophys Res Commun 2007; 358: 1136-1141.
213. Saleh AZ, Fang AT, Arch AE, Neupane D, El Fiky A, Krolewski JJ. Regulated proteolysis of the IFNaR2 subunit of the interfer-on-alpha receptor. Oncogene 2004; 23: 7076-7086.
214. Liu CX, Ranganathan S, Robinson S, Strickland DK. gamma-Secretase- mediated release of the low density lipoprotein receptor-related protein 1B intracellular domain suppresses anchorage-independent growth of neuroglioma cells. J Biol Chem 2007; 282: 7504-7511.