572
Views
41
CrossRef citations to date
0
Altmetric
Reviews

Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease

, PsyD, , MD PhD, , MD, , MD PhD, , PhD, , PhD, , MD, , PhD & , MD show all
Pages 19-37 | Published online: 14 Dec 2011

Bibliography

  • Thies W, Bleiler L. Alzheimer's association. Alzheimer's disease facts and figures. Alzheimers Dement 2011;7:208-44
  • Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007;3:186-91
  • Cummings JL. Alzheimer's disease. N Engl J Med 2004;351:56-67
  • Dubois B, Feldman HH, Jacova C, Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol 2010;9:1118-27
  • Seripa D, Panza F, Franceschi M, Non-apolipoprotein E and apolipoprotein E genetics of sporadic Alzheimer's disease. Ageing Res Rev 2009;8:214-36
  • Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991;12:383-8
  • Lesne S, Koh MT, Kotilinek L, A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;440:352-7
  • Shankar GM, Li S, Mehta TH, Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008;14:837-42
  • Panza F, Solfrizzi V, Frisardi V, Beyond the neurotransmitter-focused approach in treating Alzheimer's disease: drugs targeting beta-amyloid and tau protein. Aging Clin Exp Res 2009;21:386-406
  • Frisardi V, Solfrizzi V, Imbimbo PB, Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid. Curr Alzheimer Res 2010;7:40-55
  • Mangialasche F, Solomon A, Winblad B, Alzheimer's disease: clinical trials and drug development. Lancet Neurol 2010;9:702-16
  • Barten DM, Albright CF. Therapeutic strategies for Alzheimer's disease. Mol Neurobiol 2008;37:171-86
  • Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 2010;6:108-19
  • Panza F, Frisardi V, Imbimbo BP, Bapineuzumab: anti-beta-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. Immunotherapy 2010;2:767-82
  • Lannfelt L, Blennow K, Zetterberg H, PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2008;7:779-86
  • Faux NG, Ritchie CW, Gunn A, PBT2 rapidly improves cognition in Alzheimer's disease: additional Phase II analyses. J Alzheimers Dis 2010;20:509-16
  • Ghosh AK, Gemma S, Tang J. Beta-Secretase as a therapeutic target for Alzheimer's disease. Neurotherapeutics 2008;5:399-408
  • Imbimbo BP, Giardina GA. gamma-secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes. Curr Top Med Chem 2011;11:1555-70
  • Tomita T. Secretase inhibitors and modulators for Alzheimer's disease treatment. Expert Rev Neurother 2009;9:661-79
  • Panza F, Solfrizzi V, Frisardi V, Disease-modifying approach to the treatment of Alzheimer's disease: from alpha-secretase activators to gamma-secretase inhibitors and modulators. Drugs Aging 2009;26:537-55
  • Vellas B, Sol O, Snyder PJ, EHT0202 in Alzheimer's disease: A 3-Month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res 2011;8:203-12
  • McCarthy JV, Twomey C, Wujek P. Presenilin-dependent regulated intramembrane proteolysis and gamma-secretase activity. Cell Mol Life Sci 2009;66:1534-55
  • Guardia-Laguarta C, Pera M, Lleo A. gamma-Secretase as a therapeutic target in Alzheimer's Disease. Curr Drug Targets 2010;11:506-17
  • Haapasalo A, Kovacs DM. The many substrates of presenilin/gamma-secretase. J Alzheimers Dis 2011;25:3-28
  • Lleo A, Saura CA. gamma-secretase substrates and their implications for drug development in Alzheimer's disease. Curr Top Med Chem 2011;11:1513-27
  • De Strooper B, Saftig P, Craessaerts K, Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998;391:387-90
  • Wolfe MS, Xia W, Ostaszewski BL, Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999;398:513-17
  • Yu G, Nishimura M, Arawaka S, Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000;407:48-54
  • Bentahir M, Nyabi O, Verhamme J, Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 2006;96:732-42
  • Lleo A, Berezovska O, Growdon JH, Hyman BT. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry 2004;12:146-56
  • Panza F, Frisardi V, Imbimbo BP, Review: gamma-Secretase inhibitors for the treatment of Alzheimer's disease: the current state. CNS Neurosci Ther 2010;16:272-84
  • Lleo A. Activity of gamma-secretase on substrates other than APP. Curr Top Med Chem 2008;8:9-16
  • Petit A, Bihel F, Alves da Costa C, New protease inhibitors prevent gamma-secretase-mediated production of Abeta40/42 without affecting Notch cleavage. Nat Cell Biol 2001;3:507-11
  • Weggen S, Eriksen JL, Das P, A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212-16
  • Sagi SA, Weggen S, Eriksen J, The noncyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of kB kinase, and NFkB, do not reduce amyloid-beta 42 production. J Biol Chem 2003;278:31825-30
  • Eriksen JL, Sagi SA, Smith TE, NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta42 in vivo. J Clin Invest 2003;112:440-9
  • Peretto I, Radaelli S, Parini C, Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid1-42 secretion. J Med Chem 2005;48:5705-20
  • Lleo A, Berezovska O, Herl L, Nonsteroidal anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation. Nat Med 2004;10:1065-6
  • Takahashi Y, Hayashi I, Tominari Y, Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J Biol Chem 2003;278:18664-70
  • Kukar T, Murphy MP, Eriksen JL, Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production. Nat Med 2005;11:545-50
  • Czech C, Burns MP, Vardanian L, Cholesterol independent effect of LXR agonist TO-901317 on gamma-secretase. J Neurochem 2007;101:929-36
  • Kukar TL, Ladd TB, Bann MA, Substrate-targeting gamma-secretase modulators. Nature 2008;453:925-9
  • Richter L, Munter LM, Ness J, Amyloid beta 42 peptide (Abeta42)-lowering compounds directly bind to Abeta and interfere with amyloid precursor protein (APP) transmembrane dimerization. Proc Natl Acad Sci USA 2010;107:14597-602
  • Ohki Y, Higo T, Uemura K, Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J 2011; Epub ahead of print
  • Wolfe MS. Gamma-secretase modulators. Curr Alzheimer Res 2007;4:571-3
  • Peretto I, La Porta E. gamma-Secretase modulation and its promise for Alzheimer's disease: a medicinal chemistry perspective. Curr Top Med Chem 2008;8:38-46
  • Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science 2008;305:1119-23
  • Borchelt DR, Thinakaran G, Eckman CB, Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 2008;17:1005-13
  • Citron M, Westaway D, Xia W, Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 1997;3:67-72
  • Tomita T, Maruyama K, Saido TC, The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue. Proc Natl Acad Sci USA 1997;94:2025-30
  • Zhang Z, Nadeau P, Song W, Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2000;2:463-5
  • Armogida M, Petit A, Vincent B, Endogenous beta-amyloid production in presenilin deficient embryonic mouse fibroblasts. Nat Cell Biol 2001;3:1030-3
  • Wilson CA, Doms RW, Zheng H, Lee VM. Presenilins are not required for Ab42 production in the early secretory pathway. Nat Neurosci 2002;5:849-55
  • Lai MT, Crouthamel MC, DiMuzio J, A presenilin-independent aspartyl protease prefers the gamma-42 site cleavage. J Neurochem 2006;96:118-25
  • Yagishita S, Futai E, Ishiura S. In vitro reconstitution of gamma-secretase activity using yeast microsomes. Biochem Biophys Res Commun 2008;377:141-5
  • Sevalle J, Ayral E, Hernandez JF, Pharmacological evidences for DFK167-sensitive presenilin-independent gamma-secretase-like activity. J Neurochem 2009;110:275-83
  • Dovey HF, John V, Anderson JP, Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001;76:173-81
  • Kreft AF, Martone R, Porte A. Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease. J Med Chem 2009;52:6169-88
  • Capell A, Grunberg J, Pesold B, The 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;273:3205-11
  • Yu G, Chen F, Levesque G, The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J Biol Chem 1998;273:16470-5
  • Yu G, Nishimura M, Arawaka S, Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000;407:48-54
  • 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;99:8666-71
  • Chavez-Gutierrez L, Tolia A, Maes E, Glu (332) in the nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity. J Biol Chem 2008;283:20096-105
  • Shah S, Lee SF, Tabuchi K, Nicastrin functions as a gamma-secretase-substrate receptor. Cell 2005;122:435-47
  • Francis R, McGrath G, Zhang J, 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
  • Niimura M, Isoo N, Takasugi N, 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
  • Serneels L, Van Biervliet J, Craessaerts K, gamma-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 2009;324:639-42
  • Shirotani K, Edbauer D, Prokop S, Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 2004;279:41340-5
  • Hebert SS, Serneels L, Dejaegere T, Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol Dis 2004;17:260-72
  • 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
  • Serneels L, Dejaegere T, Craessaerts K, Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc Natl Acad Sci USA 2005;102:1719-24
  • Lai MT, Chen E, Crouthamel MC, Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem 2003;278:22475-81
  • Dejaegere T, Serneels L, Schafer MK, 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
  • Shirotani K, Tomioka M, Kremmer E, 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
  • Crystal AS, Morais VA, Pierson TC, Membrane topology of gamma-secretase component PEN-2. J Biol Chem 2003;278:20117-23
  • Bammens L, Chavez-Gutierrez L, Tolia A, Functional and topological analysis of Pen-2, the fourth subunit of the gamma-secretase complex. J Biol Chem 2011;286:12271-82
  • Gu Y, Chen F, Sanjo N, 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;278:7374-80
  • Prokop S, Shirotani K, Edbauer D, Requirement of PEN-2 for stabilization of the presenilin N-/Cterminal fragment heterodimer within the gamma-secretase complex. J Biol Chem 2004;279:23255-61
  • Kim SH, Sisodia SS. A sequence within the first transmembrane domain of PEN-2 is critical for PEN-2-mediated endoproteolysis of presenilin 1. J Biol Chem 2005;280:1992-2001
  • Sato T, Diehl TS, Narayanan S, Active gamma-secretase complexes contain only one of each component. J Biol Chem 2007;282:33985-93
  • Lazarov VK, Fraering PC, Ye W, Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci USA 2006;103:6889-94
  • Ogura T, Mio K, Hayashi I, Three-dimensional structure of the gamma-secretase complex. Biochem Biophys Res Commun 2006;343:525-34
  • Osenkowski P, Li H, Ye W, Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol 2009;385:642-52
  • De Strooper B, Annaert W, Cupers P, A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999;398:518-22
  • Sestan N, Artavanis-Tsakonas S, Rakic P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 1999;286:741-6
  • Marambaud P, Wen PH, Dutt A, A CBP binding transcriptional repressor produced by the PS1/gamma-cleavage of ncadherin is inhibited by PS1 FAD mutations. Cell 2003;114:635-45
  • Ni CY, Murphy MP, Golde TE, Carpenter G. gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001;294:2179-81
  • Muller T, Meyer HE, Egensperger R, Marcus K. The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer's disease. Prog Neurobiol 2008;85:393-406
  • Wong GT, Manfra D, Poulet FM, 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 2004;279:2876-82
  • Milano J, McKay J, Dagenais C, Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 2004;82:341-58
  • Shih Ie M, Wang TL. Notch signaling, ô -secretase inhibitors, and cancer therapy. Cancer Res 2007;67:1879-82
  • Lewis HD, Perez Revuelta BI, Nadin A, Catalytic site directed gamma-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and beta-APP cleavages. Biochemistry 2003;42:7580-6
  • Maillard I, Adler SH, Pear WS. Notch and the immune system. Immunity 2003;19:781-91
  • Stanger BZ, Datar R, Murtaugh LC, Melton DA. Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci USA 2005;102:12443-8
  • Panelos J, Massi D. Emerging role of Notch signaling in epidermal differentiation and skin cancer. Cancer Biol Ther 2009;8:1986-93
  • Searfoss GH, Jordan WH, Calligaro DO, Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 2003;278:46107-16
  • Lathia JD, Mattson MP, Cheng A. Notch: from neural development to neurological disorders. J Neurochem 2008;107:1471-81
  • Costa RM, Honjo T, Silva AJ. Learning and memory deficits in Notch mutant mice. Curr Biol 2003;13:1348-54
  • Wang Y, Chan SL, Miele L, Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA 2004;101:9458-62
  • Olson RE, Albright CF. Recent progress in the medicinal chemistry of gamma-secretase inhibitors. Curr Top Med Chem 2008;8:17-33
  • Li YM, Xu M, Lai MT, Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 2000;405:689-94
  • Esler WP, Kimberly WT, Ostaszewski BL, Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol 2000;2:428-34
  • Imbimbo BP, Speroni F. beta-Amyloid Therapeutic Strategies for Alzheimer's Disease. In: Abraham DJ, editor. Burger's Medicinal Chemistry and Drug Discovery. 6th edition. John Wiley & Sons, Inc; Hoboken: 2005. p. 1-115
  • Comery TA, Martone RL, Aschmies S, Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease. J Neurosci 2005;25:8898-902
  • Imbimbo BP. Alzheimer's disease: gamma-Secretase inhibitors. Drug Discov Today Ther Strateg 2008;5:169-75
  • Best JD, Jay MT, Otu F, Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]. J Pharmacol Exp Ther 2005;313:902-8
  • Abramowski D, Wiederhold KH, Furrer U, Dynamics of Abeta turnover and deposition in different beta-amyloid precursor protein transgenic mouse models following gamma-secretase inhibition. J Pharmacol Exp Ther 2008;327:411-24
  • Garcia-Alloza M, Subramanian M, Thyssen D, Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575. Mol Neurodegener 2009;4:19
  • Gitter BD, Czilli DL, Li W, A. Stereoselective inhibition of amyloid beta peptide secretion by LY450139 dihydrate, a novel functional gamma secretase inhibitor [abstract P4-339]. Neurobiol Aging 2004;25(Suppl 2):S571
  • Boggs LN, Fuson SF, Gitter BD, In vivo characterization of LY450139, a novel, stereoselective, functional gamma-secretase inhibitor [abstract P1-419]. Neurobiol Aging 2004;25(Suppl 2):S218
  • May PC, Yang Z, Li W, Multi-compartmental pharmacodynamic assessment of the functional gamma-secretase inhibitor LY450139 in PDAPP transgenic mice and non-transgenic mice [abstract O3-06-07]. Neurobiol Aging 2004;25(Suppl 25):65
  • Lanz TA, Karmilowicz MJ, Wood KM, Concentration-dependent modulation of Abeta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 2006;319:924-33
  • Cocke PJ, Boggs LN, Ness DK, May PC. Comparison of cisternal and lumbar cerebrospinal fluid amyloid beta concentrations following oral administration of LY450139 dihydrate to Beagle dogs [abstract P1-017]. Alzheimers Dement 2008;4(Suppl 2):T210
  • Ness DK, Boggs LN, Hepburn DL, Reduced beta-amyloid burden, increased C-99 concentrations and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate daily by gavage for 5 months [abstract P2-053]. Neurobiol Aging 2004;25(Suppl 2):S238
  • Imbimbo BP, Peretto I. Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer's disease. Curr Opin Investig Drugs 2009;10:721-30
  • Bittner T, Fuhrmann M, Burgold S, gamma-Secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J Neurosci 2009;29:10405-9
  • Siemers ER, Dean RA, Friedrich S, Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 2007;30:317-25
  • Siemers E, Skinner M, Dean RA, Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005;28:126-32
  • Siemers ER, Quinn JF, Kaye J, Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006;66:602-4
  • Fleisher AS, Raman R, Siemers ER, Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch Neurol 2008;65:1031-8
  • Bateman RJ, Siemers ER, Mawuenyega KG, A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 2009;66:48-54
  • ClinicalTrial.gov. Effect of LY450139 on the Long Term Progression of Alzheimer's Disease. Available from: http://clinicaltrials.gov/ct2/show/NCT00594568?term=LY450139&rank=3 [Last accessed 4 October 2011]
  • ClinicalTrial.gov. Effects of LY450139, on the Progression of Alzheimer's Disease as Compared With Placebo (IDENTITY-2). Available from: http://clinicaltrials.gov/ct2/show/NCT00762411?term=LY450139&rank=2 [Last accessed 4 October 2011]
  • ClinicalTrial.gov. A Study of Semagacestat for Alzheimer's Patients (Identity XT). Available from: http://clinicaltrials.gov/ct2/show/NCT01035138?term=LY450139&rank=5 [Last accessed 4 October 2011]
  • Siemers ER. Update on the semagacestat program. 3rd Conference - Clinical Trials on Alzheimer's Disease; 3 – 5 November 2010;Toulouse
  • Ross JS, Imbimbo BP. Are gamma-secretase inhibitors detrimental for Alzheimer's disease patients? J Alzheimers Dis 2010;22:401-4
  • Martone RL, Zhou H, Atchison K, Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther 2009;331:598-608
  • Frick G, Raje S, Wan H, GSI-953, a potent and selective gamma-secretase inhibitor - modulation of beta amyloid peptides and plasma and cerebrospinal fluid pharmacokinetic/ pharmacodynamic relationships in humans [abstract P4-366]. Alzheimers Dement 2008;4(Suppl 2):T781
  • Wan H, Bard J, Martone R, GSI-953, a potent and selective gamma-secretase inhibitor, modulates Abeta peptides in mice and humans: translating the PK/PD biomarker relationships in different biological compartments between rodent and human [abstract P2-101]. Alzheimers Dement 2008;4(Suppl 2):T548
  • Gillman KW, Starrett JE, Parker MF, Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable gamma-secretase inhibitor. ACS Med Chem Lett 2010;1:120-4
  • Gillman KW, Starrett JE, Parker MF, BMS-708163, a potent and selective gamma-secretase inhibitor, decreases CSF Abeta at safe and tolerable doses in animals and humans [abstract HT-01-05]. 11th International Conference on Alzheimer's Disease (ICAD);26 – 31 July 2008;Chicago, IL, USA
  • Tong G, Castaneda L, Wang JS, A study to evaluate the effects of single oral doses of BMS-708163 in the cerebrospinal fluid of healthy young men [abstract O3-07-07]. Alzheimers Dement 2010;6(Suppl 1):S143
  • Wang JS, Castaneda L, Sverdlov A, A placebo-controlled, ascending, multiple-dose study to evaluate the safety, pharmacokinetics (P) and pharmacodynamics (PD) of BMS-708163 in healthy young and elderly subjects [abstract P3-303]. Alzheimers Dement 2010;6(Suppl 1):S540
  • ClinicalTrial.gov. A Phase II, Multicenter, Double Blind, Placebo-Controlled Safety, Tolerability Study of BMS-708163 in Patients With Mild to Moderate Alzheimer's Disease. Available from: http://clinicaltrials.gov/ct2/show/NCT00810147?term=NCT00810147&rank=1 [Last accessed 4 October 2011]
  • Salloway S, Coric V, Mark Brody M, Safety and tolerability of BMS-708163 in a phase II study in mild-to-moderate Alzheimer's disease [abstract O4-06-08]. Alzheimers Dement 2011;7(Suppl 4):S695-6
  • Albright C, Andreasen N, Minthon L, The gamma-secretase inhibitor BMS-708163 causes dose-dependent reductions in CSF Abeta40 levels in patients with mild-to-moderate Alzheimer's Disease (AD) [abstract P2-015]. Alzheimers Dement 2011;7(Suppl 4):S311
  • ClinicalTrial.gov. A Multicenter, Double Blind, Placebo-Controlled, Safety and Tolerability Study of BMS-708163 in Patients With Prodromal Alzheimer's Disease. Available from: http://clinicaltrials.gov/ct2/show/NCT00810147?term=BMS-708163&rank=6 [Last accessed 4 October 2011]
  • Kambhampaty A. Alzheimer's Disease Snapshot. BioPharm Insight; Kimberly Ha: 2011
  • Brigham E, Quinn K, Kwong G, Pharmacokinetic and pharmacodynamic investigation of ELND006, a novel APP-selective gamma-secretase inhibitor, on amyloid-beta concentrations in the brain, CSF and plasma of multiple nonclinical species following oral administration [abstract P3-320]. Alzheimers Dement 2010;6(Suppl 1):S546
  • Brigham E, Quinn K, Motter R, Effects of single and multiple dose oral administration of ELND006, a novel APP-selective gamma-secretase inhibitor, on amyloid-beta concentrations in the brain and CSF of cynomolgus monkeys [abstract P3-322]. Alzheimers Dement 2010;6(Suppl 1):S546
  • Schroeter A, Brigham E, Motter R, APP-selective gamma-secretase inhibitor ELND006 effects on brain parenchymal and vascular amyloid-beta in the PDAPP mouse model of Alzheimer's disease [abstract P3-321]. Alzheimers Dement 2010;6(Suppl 1):S546
  • Lanz TA, Wood KM, Richter KE, Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther 2010;334:269-77
  • Brodney M. Discovery of PF-3084014: a novel gamma-secretase inhibitor for the treatment of Alzheimer's disease [abstract MEDI 233]. 238th ACS National Meeting; 16 – 20 August 2009;Washington, DC
  • Qui R, Willavize S, Fullerion T, Gastonguay MR. Modeling and simulation of plasma Abeta in humans after multiple oral doses of Pf-3084014, a potent gamma-secretase inhibitor [abstract P1-261]. Alzheimers Dement 2009;5(Suppl 1):P253
  • ClinicalTrial.gov. A Trial In Patients With Advanced Cancer And Leukemia. Available from: http://clinicaltrials.gov/ct2/show/NCT00878189?term=NCT00878189&rank=1 [Last accessed 4 October 2011]
  • Morimoto B. Drug Development for Neurodegenerative Diseases – a Marcus Evans Conference. IDdb Meeting Report; 7 – 8April 2009;Boston, MA
  • Rosen LB, Stone JA, Plump A, The gamma-secretase inhibitor MK-0752 acutely and significantly reduces CSF Abeta40 concentrations in humans [Abstract O4-03-02]. Alzheimers Dement 2006;2(Suppl 1):S79
  • Deangelo DJ, Stone RM, Silverman LB, 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;24(Suppl 18):6585
  • Krop IE, Kosh M, Fearen I, Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors. J Clin Oncol 2006;24(Suppl 18):10574
  • ClinicalTrial.gov. Phase I/II Study of MK-0752 Followed by Docetaxel in Advanced or Metastatic Breast Cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT00645333?term=NCT00645333&rank=1 [Last accessed 4 October 2011]
  • ClinicalTrial.gov. Study Of MK-0752 In Combination With Tamoxifen Or Letrozole to Treat Early Stage Breast Cancer. Available from: http://clinicaltrials.gov/ct2/show/NCT00756717?term=NCT00756717&rank=1 [Last accessed 4 October 2011]
  • Minati L, Edginton T, Bruzzone MG, Giaccone G. Current concepts in Alzheimer's disease: a multidisciplinary review. Am J Alzheimers Dis Other Demen 2009;24:95-121
  • Xia X, Qian S, Soriano S, Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci USA 2001;98:10863-8
  • He G, Luo W, Li P, gamma-Secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 2010;467:95-8
  • Chen F, Hasegawa H, Schmitt-Ulms G, TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 2006;440:1208-12
  • Thathiah A, Spittaels K, Hoffmann M, The orphan G protein-coupled receptor 3 modulates amyloidbeta peptide generation in neurons. Science 2009;323:946-51
  • Checler F, Dunys J, Pardossi-Piquard R, Alves da Costa C. p53 is regulated by and regulates members of the gamma-secretase complex. Neurodegener Dis 2010;7:50-5
  • Goodger ZV, Rajendran L, Trutzel A, Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci 2009;122:3703-14
  • Muller T, Meyer HE, Egensperger R, Marcus K. The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer's disease. Prog Neurobiol 2008;85:393-406
  • Chang WP, Koelsch G, Wong S, In vivo inhibition of Abeta production by memapsin 2 (betasecretase) inhibitors. J Neurochem 2004;89:1409-16
  • Kim J, Onstead L, Randle S, Abeta40 inhibits amyloid deposition in vivo. J Neurosci 2007;27:627-33
  • Mitani T, Yarimizu J, Saita K, Amelioration of Cognitive Deficits in APP Transgenic Mice with Subchronic Treatment of a gamma-Secretase Modulator but not Inhibitors [poster 419]. AD/PD 2011; Barcelona, Spain: 2011
  • Struble RG, Ala T, Patrylo PR, Is brain amyloid production a cause or a result of dementia of the Alzheimer's type? J Alzheimers Dis 2010;22:393-9
  • Vossel KA, Zhang K, Brodbeck J, Tau reduction prevents Abeta-induced defects in axonal transport. Science 2010;330:198
  • Duce JA, Tsatsanis A, Cater MA, Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 2010;142:857-67
  • Dubois B, Feldman HH, Jacova C, Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734-46
  • McKhann GM, Knopman DS, Chertkow H, The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263-9
  • Albert MS, Dekosky ST, Dickson D, The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:270-9
  • Sperling RA, Aisen PS, Beckett LA, Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:280-92
  • Weiner MW, Aisen PS, Jack CR Jr, Alzheimer's Disease Neuroimaging Initiative. The Alzheimer's disease neuroimaging initiative: progress report and future plans. Alzheimers Dement 2010;6:202-11

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.