γ-Secretase modulator in Alzheimer's Disease: Shifting the end

Journal of Alzheimer's Disease

Volumn 31, Issue 4, 2012, Pages 685-696

  Xia, Weiming ^a   Wong, Stephen T ^b   Hanlon, Eugene ^a   Morin, Peter ^a  

^a DEPARTMENT OF VETERANS AFFAIRS   (United States)

^b HOUSTON METHODIST RESEARCH INSTITUTE   (United States)

Author keywords

Alzheimer's disease; amyloid; inhibitor; modulator; Notch; presenilin; secretase

Indexed keywords

AMYLOID BETA PROTEIN[1-42]; AMYLOID PRECURSOR PROTEIN; AVAGACESTAT; GAMMA SECRETASE; GAMMA SECRETASE INHIBITOR; IMATINIB; JNJ 40418677; PRESENILIN; SEMAGACESTAT; TARENFLURBIL; UNCLASSIFIED DRUG; UVOMORULIN;

ALZHEIMER DISEASE; BLOOD BRAIN BARRIER; CARBOXY TERMINAL SEQUENCE; CEREBROSPINAL FLUID; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG EXPOSURE; DRUG STRUCTURE; HUMAN; IC 50; NEUROBLASTOMA CELL; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PLASMA PROTEIN BINDING; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN SYNTHESIS; REVIEW;

EID: 84866322498     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-2012-120751     Document Type: Review

References (77)

1. Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399(Supp), A23-A31.
2. Hutton M, Lendon C, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Peterson R, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon J, Nowotny P, Che L, Norton J, Morris J, Ree L, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd P, Hayward N, Kwok J, Schofield P, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra B, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P (1998) Association of missense and 5-splice-site mutations in tau with the inherited FTDP-17. Nature 393, 702-705.
3. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487-1491.
4. Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491-1495.
5. Haass C, Schlossmacher MG, HungAY,Vigo-Pelfrey C,Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ (1992) Amyloid -peptide is produced by cultured cells during normal metabolism. Nature 359, 322-325.
6. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai X, McKay DM, Tintner R, Frangione B, Younkin SG (1992) Production of the Alzheimer amyloid protein by normal proteolytic processing. Science 258, 126-129.
7. Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693-4697.
8. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539.
9. WalshDM,Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 44, 181-193.
10. 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 (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407, 48-54.
11. Chen F, Yu G, Arawaka S, Nishimura M, Kawarai T, Yu H, Tandon A, Supala A, Song Y, Rogaeva E, Milman P, Sato C, Yu C, Janus C, Lee J, Song L, Zhang L, Fraser P, St George-Hyslop P (2001) Nicastrin binds to membrane-tethered Notch. Nat Cell Biol 3, 751-754.
12. Goutte C, Tsunozaki M, HaleVA, Priess JR (2002) APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 99, 775-779.
13. Francis R, McGrath G, Zhang J, Ruddy D, 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 (2002) aph-1 and pen-2 are required for Notch pathway signaling, g-secretase cleavage of bAPP and presenilin protein accumulation. Dev Cell 3, 85-97.
14. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and -secretase activity. Nature 398, 513-517.
15. Tanzi RE, Bertram L (2001) New frontiers in Alzheimer's disease genetics. Neuron 32, 181-184.
16. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 278, 46107-46116.
17. 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 (2004) Chronic treatment with the gamma-secretase inhibitor LY-411, 575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279, 12876-12882.
18. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, May PC (2005) Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 28, 126-132.
19. Panelos J, Massi D (2009) Emerging role of Notch signaling in epidermal differentiation and skin cancer. Cancer Biol Ther 8, 1986-1993.
20. Gillman KW, Starrett JE, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, Williams R, Meredith JE, Burton CR, Barten DM, Toyn JH, Roberts SB, Lentz KA, Houston JG, Zaczek R, Albright CF, Decicco CP, Macor JE, Olson RE (2010) Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable g-Secretase Inhibitor. ACS Med Chem Lett 1, 120-124.
21. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC (2012) Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral gamma-secretase inhibitor BMS-708163 (Avagacestat): Tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther 34, 654-667.
22. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414, 212-216.
23. Oehlrich D, Berthelot DJC, Gijsen HJM (2011) -Secretase modulators as potential disease modifying anti-Alzheimer's drugs. J Med Chem 54, 669-698.
24. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 112, 440-449.
25. Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH (2007) Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord 21, 292-299.
26. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH (2009) Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease:Arandomized controlled trial. JAMA 302, 2557-2564.
27. Imbimbo BP, Del Giudice E, Cenacchi V, Volta R, Villetti G, Facchinetti F, Riccardi B, Puccini P, Moretto N, Grassi F, Ottonello S, Leon A (2007) In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents. Pharmacol Res 55, 318-328.
28. Imbimbo BP, Hutter-Paier B, Villetti G, Facchinetti F, Cenacchi V, Volta R, Lanzillotta A, Pizzi M, Windisch M (2009) CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol 156, 982-993.
29. Imbimbo BP, Giardino L, Sivilia S, Giuliani A, Gusciglio M, Pietrini V, Del Giudice E, D'Arrigo A, Leon A, Villetti G, Calza L (2010) CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 20, 159-173.
30. Hall A, Elliott RL, Giblin GM, Hussain I, Musgrave J, Naylor A, Sasse R, Smith B (2010) Piperidine-derived gamma-secretase modulators. Bioorg Med Chem Lett 20, 1306-1311.
31. Hussain I, Harrison DC, Hawkins J, Chapman T, Marshall I, Facci L, Ahmed S, Brackenborough K, Skaper SD, Mead TL, Smith BB, Giblin GM, Hall A, Gonzalez MI, Richardson JC (2011) TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to gamma-secretase modulation and amyloid-beta lowering by GSM-10 h. Neurodegener Dis 8, 15-24.
32. Hawkins J, Harrison DC, Ahmed S, Davis RP, Chapman T, Marshall I, Smith B, Mead TL, Medhurst A, Giblin GM, Hall A, Gonzalez MI, Richardson J, Hussain I (2011) Dynamics of Abeta42 reduction in plasma, CSF and brain of rats treated with the gamma-secretase modulator, GSM-10 h. Neurodegener Dis 8, 455-464.
33. Ohki Y, Higo T, Uemura K, Shimada N, Osawa S, Berezovska O, Yokoshima S, Fukuyama T, Tomita T, Iwatsubo T (2011) Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J 30, 4815-4824.
34. Page RM, Baumann K, Tomioka M, Perez-Revuelta BI, Fukumori A, Jacobsen H, Flohr A, LuebbersT,OzmenL, Steiner H, Haass C (2008) Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem 283, 677-683.
35. Rogers K, Chesworth R, Felsenstein K, Shapiro G, Albayya F, Tu Z, Spaulding D, Catana F, Hrdlicka L, Nolan S, Wen M, Yang Z, Vulsteke V, Patzke H, Koenig G, DeStrooper B, Ahlijanian M (2009) Putative gamma secretase modulators lowerA42 in multiple in vitro and in vivo models. Alzheimers Dement 5(Suppl), S428-S429.
36. Felsenstein KM, Spaulding D, Yang Z, Hodgdon H, Costa D, Nolan S, Wen M, Lee W, Hrdlicka L, Catana F, Albayya F, Tu Z, Patzke H, Chesworth R, Shapiro G, Zaninovic I, Ahlijanian M, Koenig G, Rogers K (2010) Pharmacokinetic and pharmacodynamic analysis of the gamma-secretase modulator (GSM) EVP-0015962. Alzheimers Dement 6(Suppl), S538.
37. Rogers K, Leventhal L, Hopp S, Miller M-J, Zhiyong Y, Hrdlicka L, Lee W, Hodgdon H, Nolan S, Wen M, Koperniak T, Spaulding D, Catana F, Chesworth R, Shapiro G, Costa D, Ahlijanian M, Koenig G, Felsenstein K (2010) The gamma secretase modulator EVP-0015962 improves cognitive deficits in Tg2576 mice concomitant with decreases in A42. Alzheimers Dement 6(Suppl), e26-e27.
38. Van Broeck B, Chen JM, Treton G, Desmidt M, Hopf C, Ramsden N, Karran E, Mercken M, RowleyA(2011) Chronic treatment with a novel gamma-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer's disease. Br J Pharmacol 163, 375-389.
39. Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E, Zhang X, Ahn K, Nguyen P, Comer D, Mao L, Yu C, Pleynet D, Digregorio PJ, Velicelebi G, Stauderman KA, Comer WT, MobleyWC, Li YM, Sisodia SS, Tanzi RE,Wagner SL (2010) Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67, 769-780.
40. Hashimoto T, Ishibashi A, Hagiwara H, Murata Y, Takenaka O, Miyagawa T (2010) E2012: A novel gamma-secretase modulator-pharmacology part. Alzheimers Dement 6(Suppl), S242.
41. Amino H, Hagiwara H, Murata Y, Watanabe H, Sasaki T, Miyagawa T (2010) E2012: A novel gamma-secretase modulator-mechanism of action. Alzheimers Dement 6(Suppl), S541-S542.
42. Caldwell JP, Bennett CE, McCracken TM, Mazzola RD, Bara T, Buevich A, Burnett DA, Chu I, Cohen-Williams M, Josein H, Hyde L, Lee J, McKittrick B, Song L, Terracina G, Voigt J, Zhang L, Zhu Z (2010) Iminoheterocycles as gammasecretase modulators. Bioorg Med Chem Lett 20, 5380-5384.
43. Huang X, Aslanian R, Zhou W, Zhu X, Qin J, Greenlee W, Zhu Z, Zhang L, Hyde L, Chu I, Cohen-Williams M, Palani A (2010) The discovery of pyridone and pyridazone heterocycles as -secretase modulators. ACS Med Chem Lett 1, 184-187.
44. Fischer C, Shah S, Hughes BL, Nikov GN, Crispino JL, Middleton RE, Szewczak AA, Munoz B, Shearman MS (2011) Quinazolinones as gamma-secretase modulators. Bioorg Med Chem Lett 21, 773-776.
45. Fischer C, Zultanski SL, Zhou H, Methot JL, Brown WC, Mampreian DM, Schell AJ, Shah S, Nuthall H, Hughes BL, Smotrov N, Kenific CM, Cruz JC, Walker D, Bouthillette M, Nikov GN, Savage DF, Jeliazkova-Mecheva VV, Diaz D, Szewczak AA, Bays N, Middleton RE, Munoz B, Shearman MS (2011) Triazoles as gamma-secretase modulators. Bioorg Med Chem Lett 21, 4083-4087.
46. Rivkin A, Ahearn SP, Chichetti SM, Hamblett CL, Garcia Y, Martinez M, Hubbs JL, Reutershan MH, Daniels MH, Siliphaivanh P, Otte KM, Li C, Rosenau A, Surdi LM, Jung J, Hughes BL, Crispino JL, Nikov GN, Middleton RE, Moxham CM, Szewczak AA, Shah S, Moy LY, Kenific CM, Tanga F, Cruz JC, Andrade P, Angagaw MH, Shomer NH, Miller T, Munoz B, Shearman MS (2010) Purine derivatives as potent gamma-secretase modulators. Bioorg Med Chem Lett 20, 2279-2282.
47. Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R, Maharvi GM, Healy B, Chapman R, Welzel AT, Price RW, Moore B, Rangachari V, Cusack B, Eriksen J, Jansen-West K, Verbeeck C, Yager D, Eckman C, Ye W, Sagi S, Cottrell BA, Torpey J, Rosenberry TL, Fauq A, Wolfe MS, Schmidt B, Walsh DM, Koo EH, Golde TE (2008) Substrate-targeting gamma-secretase modulators. Nature 453, 925-929.
48. Beel AJ, Barrett P, Schnier PD, Hitchcock SA, Bagal D, Sanders CR, Jordan JB (2009) Nonspecificity of binding of gamma-secretase modulators to the amyloid precursor protein. Biochemistry 48, 11837-11839.
49. Sagi S, Lessard C,Winden K, Maruyama H,Koo J,Weggen S, KukarT, GoldeT,KooE(2011) Substrate sequence influences γ-secretase modulator activity, role of the transmembrane domain of the amyloid precursor protein. J Biol Chem 286, 39794-39803.
50. Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P (2003) Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A 100, 12444-12449.
51. Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 62, 4236-4243.
52. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938-1942.
53. Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: Insights into drug design from structure. Science 303, 1800-1805.
54. He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 467, 95-98.
55. Armulik A, Genove G, Mae M, Nisancioglu MH,Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood-brain barrier. Nature 468, 557-561.
56. Zhou S, Zhou H,Walian PJ, JapBK(2005) CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production. Proc Natl Acad Sci U S A 102, 7499-7504.
57. 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 (2006) TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 440, 1208-1212.
58. Winkler E, Hobson S, Fukumori A, Dumpelfeld B, Luebbers T, Baumann K, Haass C, Hopf C, Steiner H (2009) Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human gammasecretase. Biochemistry 48, 1183-1197.
59. Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, LaPlant Q, Ball H, Dann CE 3rd, Sudhof T, Yu G (2005) Nicastrin functions as a gamma-secretase-substrate receptor. Cell 122, 435-447.
60. Fraering PC, LaVoie MJ, Ye W, Ostaszewski BL, Kimberly WT, Selkoe DJ,Wolfe MS (2004) 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 43, 323-333.
61. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181-190.
62. Page RM, Gutsmiedl A, Fukumori A, Winkler E, Haass C, Steiner H (2010) Beta-amyloid precursor protein mutants respond to gamma-secretase modulators. J Biol Chem 285, 17798-17810.
63. Hahn S, Bruning T, Ness J, Czirr E, Baches S, Gijsen H,Korth C, Pietrzik CU, Bulic B,Weggen S (2011) Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer's disease attenuate the response of cultured cells to gamma-secretase modulators regardless of their potency and structure. J Neurochem 116, 385-395.
64. Ebke A, Luebbers T, Fukumori A, Shirotani K, Haass C, Baumann K, Steiner H (2011) Novel gamma-secretase enzyme modulators directly target presenilin protein. J Biol Chem 286, 37181-37186.
65. Crump CJ, Fish BA, Castro SV, Chau DM, Gertsik N, Ahn K, Stiff C, Pozdnyakov N, Bales KR, Johnson DS, Li YM (2011) Piperidine acetic acid based gamma-secretase modulators directly bind to Presenilin-1. ACS Chem Neurosci 2, 705-710.
66. Crump CJ, Johnson DS, Li YM (2011) Target of gammasecretase modulators, presenilin marks the spot. EMBO J 30, 4696-4698.
67. Jumpertz T, Rennhack A, Ness J, Baches S, Pietrzik CU, Bulic B, Weggen S (2012) Presenilin is the molecular target of acidic gamma-secretase modulators in living cells. PLoS One 7, e30484.
68. Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ (2008) Direct and potent regulation of gamma-secretase by its lipid microenvironment. J Biol Chem 283, 22529-22540.
69. SmithDA,DiL,KernsEH(2010) The effect of plasma protein binding on in vivo efficacy: Misconceptions in drug discovery. Nat Rev Drug Discov 9, 929-939.
70. Borghys H, Tuefferd M, Van Broeck B, Clessens E, Dillen L, Cools W, Vinken P, Straetemans R, De Ridder F, Gijsen H, Mercken M (2012) A canine model to evaluate efficacy and safety of gamma-secretase inhibitors and modulators. J Alzheimers Dis 28, 809-822.
71. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS (2012) Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482, 216-220.
72. Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L,Vanti WB, Moreno H, Abeliovich A (2011) Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. Cell 146, 359-371.
73. Osenkowski P, Li H, Ye W, Li D, Aeschbach L, Fraering PC, Wolfe MS, Selkoe DJ (2009) Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol 385, 642-652.
74. Singer SJ, Dewji NN (2006) Evidence that Perutz's doublebeta-stranded subunit structure for beta-amyloids also applies to their channel-forming structures in membranes. Proc Natl Acad Sci U S A 103, 1546-1550.
75. McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, Delucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191-199.
76. Lanz TA, Karmilowicz MJ,Wood KM, Pozdnyakov N, Du P, Piotrowski MA, Brown TM, Nolan CE, Richter KE, Finley JE, Fei Q, Ebbinghaus CF, Chen YL, Spracklin DK, Tate B, Geoghegan KF, Lau LF, Auperin DD, Schachter JB (2006) Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 319, 924-933.
77. Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS (2005) gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotidebinding site. J Biol Chem 280, 41987-41996.