Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: still a viable option?

Bibliography

• Ferri CP, Prince M, Brayne C, Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-17
   PubMed Web of Science ®Google Scholar
• Alzheimer's Association. Alzheimer's disease facts and figures. Alzheimers Dement 2010;6:158-94
   PubMed Web of Science ®Google Scholar
• Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007;3:186-91
   PubMed Web of Science ®Google Scholar
• Mattson MP. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 1997;77:1081-132
   PubMed Web of Science ®Google Scholar
• Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991;12:383-8
   PubMed Web of Science ®Google Scholar
• Lesne S, Koh MT, Kotilinek L, A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;440:352-7
   PubMed Web of Science ®Google Scholar
• Shankar GM, Li S, Mehta T, Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008;14:837-42
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Imbimbo BP. Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem 2008;8:54-61
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Lleo A. Activity of gamma-secretase on substrates other than APP. Curr Top Med Chem 2008;8:9-16
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Weggen S, Eriksen JL, Das P, A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212-16
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 2010;6:108-19
   PubMed Web of Science ®Google Scholar
• Panza F, Frisardi V, Imbimbo BP, Bapineuzumab: anti-beta-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. Immunotherapy 2010;2:767-82
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Frisardi V, Solfrizzi V, Imbimbo BP, Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid. Curr Alzheimer Res 2010;7:40-55
   PubMed Web of Science ®Google Scholar
• Imbimbo BP. Why did tarenflurbil fail in Alzheimer's disease? J Alzheimers Dis 2009;17:757-60
   PubMed Web of Science ®Google Scholar
• Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science 2004;305:1119-23
   PubMed Web of Science ®Google Scholar
• Armogida M, Petit A, Vincent B, Endogenous beta-amyloid production in presenilin deficient embryonic mouse fibroblasts. Nature Cell Biol 2001;3:1030-3
   PubMed Web of Science ®Google Scholar
• Wilson CA, Doms RW, Zheng H, Presenilins are not required for Abeta42 production in the early secretory pathway. Nat Neurosci 2002;5:849-55
   PubMed Web of Science ®Google Scholar
• Lai MT, Crouthamel MC, DiMuzio J, A presenilin-independent aspartyl protease prefers the gamma-42 site cleavage. J Neurochem 2006;96:118-25
   PubMed Web of Science ®Google Scholar
• Yagishita S, Futai E, Ishiura S. In vitro reconstitution of gamma-secretase activity using yeast microsomes. Biochem Biophys Res Commun 2008;377:141-5
   PubMed Web of Science ®Google Scholar
• Sevalle J, Ayral E, Hernandez JF, Pharmacological evidences for DFK167-sensitive presenilin-independent gamma-secretase-like activity. J Neurochem 2009;110:275-83
   PubMed Web of Science ®Google Scholar
• Dovey HF, John V, Anderson JP, Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001;76:173-81
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Yu G, Nishimura M, Arawaka S, Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000;407:48-54
   PubMed Web of Science ®Google Scholar
• Edbauer D, Winkler E, Haass C, Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Proc Natl Acad Sci USA 2002;99:8666-71
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Shah S, Lee SF, Tabuchi K, Nicastrin functions as a gamma-secretase-substrate receptor. Cell 2005;122:435-47
   PubMed Web of Science ®Google Scholar
• Crystal AS, Morais VA, Pierson TC, Membrane topology of gamma-secretase component PEN-2. J Biol Chem 2003;278:20117-23
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Serneels L, Van Biervliet J, Craessaerts K, Gamma-secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 2009;324:639-42
   PubMed Web of Science ®Google Scholar
• Osenkowski P, Li H, Ye W, Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol 2009;385:642-52
   PubMed Web of Science ®Google Scholar
• Olson RE, Albright CF. Recent progress in the medicinal chemistry of gamma-secretase inhibitors. Curr Top Med Chem 2008;8:17-33
   PubMed Web of Science ®Google Scholar
• Guardia-Laguarta C, Pera M, Lleo A. Gamma-secretase as a therapeutic target in Alzheimer's disease. Curr Drug Targets 2010;11:506-17
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Sestan N, Artavanis-Tsakonas S, Rakic P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 1999;286:741-6
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Ni CY, Murphy MP, Golde TE, Gamma-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001;294:2179-81
   PubMed Web of Science ®Google Scholar
• von Rotz RC, Kohli BM, Bosset J, The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J Cell Sci 2004;117:4435-48
   PubMed Web of Science ®Google Scholar
• Alves da Costa C, Sunyach C, Pardossi-Piquard R, Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease. J Neurosci 2006;26:6377-85
   PubMed Web of Science ®Google Scholar
• Pardossi-Piquard R, Dunys J, Yu G, Neprilysin activity and expression are controlled by nicastrin. J Neurochem 2006;97:1052-6
   PubMed Web of Science ®Google Scholar
• Liu Q, Zerbinatti CV, Zhang J, Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 2007;56:66-78
   PubMed Web of Science ®Google Scholar
• Zhang YW, Wang R, Liu Q, Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci USA 2007;104:10613-18
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Imbimbo BP. Alzheimer's disease: gamma-secretase inhibitors. Drug Disc Today Ther Strateg 2008;5:169-75
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Gitter BD, Czilli DL, Li W, 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
   Google Scholar
• Boggs LN, Fuson SF, Gitter B, In vivo characterization of LY450139, a novel, stereoselective, functional gamma-secretase inhibitor [abstract P1-419]. Neurobiol Aging 2004;25(Suppl 2):S218
   Google Scholar
• 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 03-06-07]. Neurobiol Aging 2004;25(Suppl 2):S65
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Cocke PJ, Boggs LN, Ness DK, 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
   Google Scholar
• 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
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• ClinicalTrial.gov. Effect of LY450139 on the Long Term Progression of Alzheimer's Disease. Available from: http://clinicaltrials.gov/ct2/show/NCT00594568?term=NCT00594568&rank=1. [Last accessed 30 November 2010]
   Google Scholar
• 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=IDENTITY&rank=9. [Last accessed 30 November 2010]
   Google Scholar
• ClinicalTrial.gov. A Study in Semagacestat for Alzheimer's Patients (Identity XT). Available from: http://clinicaltrials.gov/ct2/show/NCT01035138?term=IDENTITY&rank=8. [Last accessed 30 November 2010]
   Google Scholar
• Siemers ER. Update on the semagacestat program. III Conference – Clinical Trials on Alzheimer's Disease; 3–5 November 2010; Toulouse
   Google Scholar
• Morimoto B. Drug Development for Neurodegenerative Diseases – a Marcus Evans Conference. IDdb Meeting Report; 7–8 April 2009; Boston, MA
   Google Scholar
• 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
   Google Scholar
• 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
   Google Scholar
• 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
   Google Scholar
• 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 30 November 2010]
   Google Scholar
• 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?intr=%22MK-0752%22&rank=4. [Last accessed 30 November 2010]
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Albright CF, Dockens R, Olson RE, 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
   Google Scholar
• 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
   Google Scholar
• Wang JS, Catenada 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
   Google Scholar
• 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 30 November 2010]
   Google Scholar
• 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/NCT00890890. [Last accessed 30 November 2010]
   Google Scholar
• Lanz TA, Wood KM, Richter KE, Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther 2010;334:269-77
   PubMed Web of Science ®Google Scholar
• 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
   Google Scholar
• Qui R, Willavize S, Fullerion T, 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
   Google Scholar
• 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 30 November 2010]
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   Google Scholar
• 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
   Google Scholar
• 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
   Google Scholar
• 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
   Google Scholar
• 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
   Google Scholar
• Martenyi F, Lowe S, Dean RA, Central and peripheral pharmacokinetics and pharmacodynamic effects of the beta-site APP cleavage enzyme (BACE1) inhibitor LY2811376 in humans [abstract P4-088]. ICAD 2010; 10–15 July 2010; Honolulu
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Maillard I, Adler SH, Pear WS. Notch and the immune system. Immunity 2003;19:781-91
   PubMed Web of Science ®Google Scholar
• Stanger BZ, Datar R, Murtaugh LC, Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci USA 2005;102:12443-8
   PubMed Web of Science ®Google Scholar
• Panelos J, Massi D. Emerging role of Notch signaling in epidermal differentiation and skin cancer. Cancer Biol Ther 2009;8:1986-93
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   Google Scholar
• Lathia JD, Mattson MP, Cheng A. Notch: from neural development to neurological disorders. J Neurochem 2008;107:1471-81
   PubMed Web of Science ®Google Scholar
• Costa RM, Honjo T, Silva AJ. Learning and memory deficits in Notch mutant mice. Curr Biol 2003;13:1348-54
   PubMed Web of Science ®Google Scholar
• Wang Y, Chan SL, Miele L, Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA 2004;101:9458-62
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• He G, Luo W, Li P, Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 2010;467:95-8
   PubMedGoogle Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Thathiah A, Spittaels K, Hoffmann M, The orphan G protein-coupled receptor 3 modulates amyloidbeta peptide generation in neurons. Science 2009;323:946-51
   PubMed Web of Science ®Google Scholar
• Checler F, Dunys J, Pardossi-Piquard R, p53 is regulated by and regulates members of the gamma-secretase complex. Neurodegener Dis 2010;7:50-5
   PubMed Web of Science ®Google Scholar
• Roperch JP, Alvaro V, Prieur S, Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression. Nat Med 1998;4:835-8
   PubMed Web of Science ®Google Scholar
• Pastorcic M, Das HK. Regulation of transcription of the human presenilin-1 gene by ets transcription factors and the p53 protooncogene. J Biol Chem 2000;275:34938-45
   PubMed Web of Science ®Google Scholar
• Dunys J, Sevalle J, Giaime E, p53-dependent control of transactivation of the Pen2 promoter by presenilins. J Cell Sci 2009;122:4003-8
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Muller T, Meyer HE, Egensperger R, 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
   PubMed Web of Science ®Google Scholar
• Kim J, Onstead L, Randle S, Abeta40 inhibits amyloid deposition in vivo. J Neurosci 2007;27:627-33
   PubMed Web of Science ®Google Scholar
• Sevalle J, Amoyel A, Robert P, Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide. J Neurochem 2009;109:248-56
   PubMed Web of Science ®Google Scholar
• Wrigley JD, Martin AC, Clarke EE, Modulation versus inhibition – selected NSAIDs can act as gamma secretase inhibitors in vitro [abstract 295.2]. 33rd Annual Meeting of Society of Neuroscience; 8–12 November 2003; New Orleans
   Google Scholar
• Terrando N, Monaco C, Ma D, Tumor necrosis factor-gamma triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA 2010;107:20518-22
   PubMed Web of Science ®Google Scholar
• Wilkinson BL, Cramer PE, Varvel NH, Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease. Neurobiol Aging 2010. [Epub ahead of print]
   Google Scholar
• Varvel NH, Bhaskar K, Kounnas MZ, NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest 2009;119:3692-702
   PubMed Web of Science ®Google Scholar
• Zhao X, Rebeck GW, Hoe HS, Tarenflurbil protection from cytotoxicity is associated with an upregulation of neurotrophins. J Alzheimers Dis 2008;15:397-407
   PubMed Web of Science ®Google Scholar
• Sanz-Blasco S, Valero RA, Rodriguez-Crespo I, Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS One 2008;3:e2718
   PubMed Web of Science ®Google Scholar
• Lichtenstein M, Carriba P, Wojciak-Stothard B, Secretase-independent and RhoGTPase/ERK/PAK regulation of cytoskeleton dynamics and motility in astrocytes by NSAIDs and derivatives. J Alzheimers Dis 2010. [Epub ahead of print]
   Google Scholar
• Vossel KA, Zhang K, Brodbeck J, Tau reduction prevents Abeta-induced defects in axonal transport. Science 2010;330:198
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Leuchter B, Ho MK, Malloy M. Alzheimer's disease: drug market poised for expansion. Goldman Sachs 2008
   Google Scholar
• Holmes C, Boche D, Wilkinson D, Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008;372:216-23
   PubMed Web of Science ®Google Scholar
• Castellani RJ, Lee HG, Siedlak SL, Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. J Alzheimers Dis 2009;18:447-52
   PubMed Web of Science ®Google Scholar
• Castellani RJ, Lee HG, Zhu X, Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 2008;67:523-31
   PubMed Web of Science ®Google Scholar
• Tampellini D, Rahman N, Gallo EF, Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta related synaptic alterations. J Neurosci 2009;29:9704-13
   PubMed Web of Science ®Google Scholar
• Abramov E, Dolev I, Fogel H, Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 2009;12:1567-76
   PubMed Web of Science ®Google Scholar
• Puzzo D, Privitera L, Leznik E, Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 2008;28:14537-45
   PubMed Web of Science ®Google Scholar
• Morley JE, Farr SA, Banks WA, A physiological role for amyloid-beta protein: enhancement of learning and memory. J Alzheimers Dis 2010;19:441-9
   PubMed Web of Science ®Google Scholar
• Bennett DA, Schneider JA, Arvanitakis Z, Neuropathology of older persons without cognitive impairment from two communitybased studies. Neurology 2006;66:1837-44
   PubMed Web of Science ®Google Scholar
• Aizenstein HJ, Nebes RD, Saxton JA, Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 2008;65:1509-17
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• John V, Beck JP, Bienkowski MJ, Human beta-secretase (BACE) and BACE inhibitors. J Med Chem 2003;46:4625-30
   PubMed Web of Science ®Google Scholar