Advanced search
Publication Cover
Expert Review of Neurotherapeutics Volume 9, 2009 - Issue 5
Submit an article Journal homepage
238
Views
108
CrossRef citations to date
0
Altmetric
Review

Secretase inhibitors and modulators for Alzheimer’s disease treatment

Taisuke Tomita Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo 113–0033, Japan. [email protected]
Pages 661-679 | Published online: 09 Jan 2014

References

  • Brookmayer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement.3(3), 186–191 (2007).
  • Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat. Rev. Mol. Cell Biol.8(2), 101–112 (2007).
  • Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci.8(9), 663–672 (2007).
  • Bertram L, Tanzi RE. Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat. Rev. Neurosci.9(10), 768–778 (2008).
  • Deuss M, Reiss K, Hartmann D. Part-time alpha;-secretases: the functional biology of ADAM 9, 10 and 17. Curr. Alzheimer Res.5(2), 187–201 (2008).
  • Suzuki N, Cheung TT, Cai XD et al. An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants. Science264(5163), 1336–1340 (1994).
  • Asami-Odaka A, Ishibashi Y, Kikuchi T, Kitada C, Suzuki N. Long amyloid β-protein secreted from wild-type human neuroblastoma IMR-32 cells. Biochemistry34(32), 10272–10278 (1995).
  • Iwatsubo T, Odaka A, Suzuki N et al. Visualization of Aβ 42(43) and Aβ 40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ 42(43). Neuron13(1), 45–53 (1994).
  • Jarrett JT, Berger EP, Lansbury PT Jr. The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry32(18), 4693–4697 (1993).
  • Citron M, Oltersdorf T, Haass C et al. Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature360(6405), 672–674 (1992).
  • Cai XD, Golde TE, Younkin SG. Release of excess amyloid β protein from a mutant amyloid β protein precursor. Science259(5094), 514–516 (1993).
  • Klein WL, Stine WB Jr, Teplow DB. Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer’s disease. Neurobiol. Aging25(5), 569–580 (2004).
  • Rovelet-Lecrux A, Hannequin D, Raux G et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet.38(1), 24–26 (2006).
  • Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science297(5580), 353–356 (2002).
  • Barten DM, Albright CF. Therapeutic strategies for Alzheimer’s disease. Mol. Neurobiol.37(2–3), 171–186 (2008).
  • Evin G, Kenche VB. BACE inhibitors as potential therapeutics for Alzheimer’s disease. Recent Patents CNS Drug Discov.2(3), 188–199 (2007).
  • Ghosh AK, Gemma S, Tang J. β-secretase as a therapeutic target for Alzheimer’s disease. Neurotherapeutics5(3), 399–408 (2008).
  • Wolfe MS. Inhibition and modulation of γ-secretase for Alzheimer’s disease. Neurotherapeutics5(3), 391–398 (2008).
  • Tomita T. At the frontline of Alzheimer’s disease treatment: γ-secretase inhibitor/modulator mechanism. Naunyn Schmiedebergs Arch. Pharmacol.377(4–6), 295–300 (2008).
  • Imbimbo BP. Therapeutic potential of γ-secretase inhibitors and modulators. Curr. Top. Med. Chem.8(1), 54–61 (2008).
  • Evin G. γ-secretase modulators: hopes and setbacks for the future of Alzheimer’s treatment. Expert Rev. Neurother.8(11), 1611–1613 (2008).
  • Stockley JH, O’Neill C. Understanding BACE1: essential protease for amyloid-β production in Alzheimer’s disease. Cell. Mol. Life Sci.65(20), 3265–3289 (2008).
  • Cole SL, Vassar R. The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. J. Biol. Chem.283(44), 29621–29625 (2008).
  • Hussain I, Powell D, Howlett DR et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci.14(6), 419–427 (1999).
  • Vassar R, Bennett BD, Babu-Khan S et al. β-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science286(5440), 735–741 (1999).
  • Sinha S, Anderson JP, Barbour R et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature402(6761), 537–540 (1999).
  • Yan R, Bienkowski MJ, Shuck ME et al. Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature402(6761), 533–537 (1999).
  • Lin X, Koelsch G, Wu S et al. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc. Natl Acad. Sci. USA97(4), 1456–1460 (2000).
  • Cai H, Wang Y, McCarthy D et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat. Neurosci.4(3), 233–234 (2001).
  • Luo Y, Bolon B, Kahn S et al. Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci.4(3), 231–232 (2001).
  • Roberds SL, Anderson J, Basi G et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum. Mol. Genet.10(12), 1317–1324 (2001).
  • Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. β-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol.59(9), 1381–1389 (2002).
  • Sun A, Koelsch G, Tang J, Bing G. Localization of β-secretase memapsin 2 in the brain of Alzheimer’s patients and normal aged controls. Exp. Neurol.175(1), 10–22 (2002).
  • Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor β-secretase in Alzheimer’s disease. Ann. Neurol.51(6), 783–786 (2002).
  • Yang LB, Lindholm K, Yan R et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat. Med.9(1), 3–4 (2003).
  • Li R, Lindholm K, Yang LB et al. Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer’s disease patients. Proc. Natl Acad. Sci. USA101(10), 3632–3637 (2004).
  • Selkoe DJ, Wolfe MS. Presenilin: running with scissors in the membrane. Cell131(2), 215–221 (2007).
  • Sherrington R, Rogaev EI, Liang Y et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature375(6534), 754–760 (1995).
  • Levy-Lahad E, Wasco W, Poorkaj P et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science269(5226), 973–977 (1995).
  • Rogaev EI, Sherrington R, Rogaeva EA 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. Nature376(6543), 775–778 (1995).
  • Scheuner D, Eckman C, Jensen M et al. Secreted amyloid β-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.2(8), 864–870 (1996).
  • Borchelt DR, Thinakaran G, Eckman CB et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ1–42/1–40 ratio in vitro and in vivo. Neuron17(5), 1005–1013 (1996).
  • Duff K, Eckman C, Zehr C et al. Increased amyloid-β 42(43) in brains of mice expressing mutant presenilin 1. Nature383(6602), 710–713 (1996).
  • Citron M, Westaway D, Xia W et al. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat. Med.3(1), 67–72 (1997).
  • Tomita T, Maruyama K, Saido TC et al. The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue. Proc. Natl Acad. Sci. USA94(5), 2025–2030 (1997).
  • De Strooper B, Saftig P, Craessaerts K et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature391(6665), 387–390 (1998).
  • Naruse S, Thinakaran G, Luo JJ et al. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron21(5), 1213–1221 (1998).
  • Herreman A, Serneels L, Annaert W et al. Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol.2(7), 461–462 (2000).
  • Zhang Z, Nadeau P, Song W et al. Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nat. Cell Biol.2(7), 463–465 (2000).
  • Li YM, Lai MT, Xu M et al. Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state. Proc. Natl Acad. Sci. USA97(11), 6138–6143 (2000).
  • Yu G, Nishimura M, Arawaka S et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature407(6800), 48–54 (2000).
  • Goutte C, Tsunozaki M, Hale VA, Priess JR. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl Acad. Sci. USA99(2), 775–779 (2002).
  • Francis R, McGrath G, Zhang J et al. aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev. Cell3(1), 85–97 (2002).
  • Chung HM, Struhl G. Nicastrin is required for presenilin-mediated transmembrane cleavage in Drosophila. Nat. Cell Biol.3(12), 1129–1132 (2001).
  • Hu Y, Ye Y, Fortini ME. Nicastrin is required for γ-secretase cleavage of the Drosophila Notch receptor. Dev. Cell2(1), 69–78 (2002).
  • Lopez-Schier H, St Johnston D. Drosophila nicastrin is essential for the intramembranous cleavage of notch. Dev. Cell2(1), 79–89 (2002).
  • Li J, Fici GJ, Mao CA et al. Positive and negative regulation of the γ-secretase activity by nicastrin in a murine model. J. Biol. Chem.278(35), 33445–33449 (2003).
  • Li T, Ma G, Cai H, Price DL, Wong PC. Nicastrin is required for assembly of presenilin/γ-secretase complexes to mediate Notch signaling and for processing and trafficking of β-amyloid precursor protein in mammals. J. Neurosci.23(8), 3272–3277 (2003).
  • Takasugi N, Tomita T, Hayashi I et al. The role of presenilin cofactors in the γ-secretase complex. Nature422(6930), 438–441 (2003).
  • Ma G, Li T, Price DL, Wong PC. APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development. J. Neurosci.25(1), 192–198 (2005).
  • Serneels L, Dejaegere T, Craessaerts K et al. Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc. Natl Acad. Sci. USA102(5), 1719–1724 (2005).
  • Edbauer D, Winkler E, Regula JT et al. Reconstitution of γ-secretase activity. Nat. Cell Biol.5(5), 486–488 (2003).
  • Kim SH, Ikeuchi T, Yu C, Sisodia SS. Regulated hyperaccumulation of presenilin-1 and the “γ-secretase” complex. Evidence for differential intramembranous processing of transmembrane subatrates. J. Biol. Chem.278(36), 33992–34002 (2003).
  • Kimberly WT, LaVoie MJ, Ostaszewski BL et al. γ-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl Acad. Sci. USA100(11), 6382–6387 (2003).
  • Hayashi I, Urano Y, Fukuda R et al. Selective reconstitution and recovery of functional γ-secretase complex on budded baculovirus particles. J. Biol. Chem.279(36), 38040–38046 (2004).
  • Wolfe MS, Xia W, Ostaszewski BL et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature398(6727), 513–517 (1999).
  • Esler WP, Kimberly WT, Ostaszewski BL et al. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat. Cell Biol.2(7), 428–434 (2000).
  • Li YM, Xu M, Lai MT et al. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature405(6787), 689–694 (2000).
  • Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science296(5576), 2215–2218 (2002).
  • Haass C, Steiner H. Alzheimer disease γ-secretase: a complex story of GxGD-type presenilin proteases. Trends Cell Biol.12(12), 556–562 (2002).
  • Urban S, Freeman M. Intramembrane proteolysis controls diverse signalling pathways throughout evolution. Curr. Opin. Genet. Dev.12(5), 512–518 (2002).
  • Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science305(5687), 1119–1123 (2004).
  • Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell100(4), 391–398 (2000).
  • Hass MR, Sato C, Kopan R, Zhao G. Presenilin: RIP and beyond. Semin. Cell Dev. Biol.20(2), 201–210 (2009).
  • Shah S, Lee SF, Tabuchi K et al. Nicastrin functions as a γ-secretase-substrate receptor. Cell122(3), 435–447 (2005).
  • Chavez-Gutierrez L, Tolia A, Maes E et al. Glu(332) in the nicastrin ectodomain is essential for γ-secretase complex maturation but not for its activity. J. Biol. Chem.283(29), 20096–20105 (2008).
  • Shirotani K, Edbauer D, Capell A et al. γ-secretase activity is associated with a conformational change of nicastrin. J. Biol. Chem.278(19), 16474–16477 (2003).
  • Ogura T, Mio K, Hayashi I et al. Three-dimensional structure of the γ-secretase complex. Biochem. Biophys. Res. Commun.343(2), 525–534 (2006).
  • LaVoie MJ, Fraering PC, Ostaszewski BL et al. Assembly of the γ-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin. J. Biol. Chem.278(39), 37213–37222 (2003).
  • Niimura M, Isoo N, Takasugi N et al. Aph-1 contributes to the stabilization and trafficking of the γ-secretase complex through mechanisms involving intermolecular and intramolecular interactions. J. Biol. Chem.280(13), 12967–12975 (2005).
  • Isoo N, Sato C, Miyashita H et al. Aβ42 overproduction associated with structural changes in the catalytic pore of γ-secretase: common effects of Pen-2 N-terminal elongation and fenofibrate. J. Biol. Chem.282(17), 12388–12396 (2007).
  • Zhou S, Zhou H, Walian PJ, Jap BK. CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer’s disease amyloid β-peptide production. Proc. Natl Acad. Sci. USA102(21), 7499–7504 (2005).
  • Chen F, Hasegawa H, Schmitt-Ulms G et al. TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature440(7088), 1208–1212 (2006).
  • Beher D, Fricker M, Nadin A et al.In vitro characterization of the presenilin-dependent γ-secretase complex using a novel affinity ligand. Biochemistry42(27), 8133–8142 (2003).
  • Winkler E, Hobson S, Fukumori A et al. Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human γ-secretase. Biochemistry DOI: 10.1021/bi801204g (2009) (Epub ahead of print).
  • Esler WP, Kimberly WT, Ostaszewski BL et al. Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a g substrate. Proc. Natl Acad. Sci. USA99(5), 2720–2725 (2002).
  • Fraering PC, Ye W, Strub JM et al. Purification and characterization of the human γ-secretase complex. Biochemistry43(30), 9774–9789 (2004).
  • Ohno M, Sametsky EA, Younkin LH et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron41(1), 27–33 (2004).
  • Laird FM, Cai H, Savonenko AV et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci.25(50), 11693–11709 (2005).
  • Ohno M, Chang L, Tseng W et al. Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1. Eur J. Neurosci.23(1), 251–260 (2006).
  • Ma H, Lesne S, Kotilinek L et al. Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. Proc. Natl Acad. Sci. USA104(19), 8167–8172 (2007).
  • Kobayashi D, Zeller M, Cole T et al.BACE1 gene deletion: impact on behavioral function in a model of Alzheimer’s disease. Neurobiol. Aging29(6), 861–873 (2008).
  • Dominguez D, Tournoy J, Hartmann D et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J. Biol. Chem.280(35), 30797–30806 (2005).
  • Hu X, Hicks CW, He W et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci.9(12), 1520–1525 (2006).
  • Willem M, Garratt AN, Novak B et al. Control of peripheral nerve myelination by the β-secretase BACE1. Science314(5799), 664–666 (2006).
  • Hu X, He W, Diaconu C et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J.22(8), 2970–2980 (2008).
  • Savonenko AV, Melnikova T, Laird FM et al. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc. Natl Acad. Sci. USA105(14), 5585–5590 (2008).
  • Dejaegere T, Serneels L, Schafer MK et al. Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc. Natl Acad. Sci. USA105(28), 9775–9780 (2008).
  • Sankaranarayanan S, Price EA, Wu G et al.In vivo β-secretase 1 inhibition leads to brain Aβ lowering and increased alpha;-secretase processing of amyloid precursor protein without effect on neuregulin-1. J. Pharmacol. Exp. Ther.324(3), 957–969 (2008).
  • McConlogue L, Buttini M, Anderson JP et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic Mice. J. Biol. Chem.282(36), 26326–26334 (2007).
  • Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature377(6547), 351–354 (1995).
  • Struhl G, Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature398(6727), 522–525 (1999).
  • Ye Y, Lukinova N, Fortini ME. Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants. Nature398(6727), 525–529 (1999).
  • Doerfler P, Shearman MS, Perlmutter RM. Presenilin-dependent γ-secretase activity modulates thymocyte development. Proc. Natl Acad. Sci. USA98(16), 9312–9317 (2001).
  • Hadland BK, Manley NR, Su D et al. γ-secretase inhibitors repress thymocyte development. Proc. Natl Acad. Sci. USA98(13), 7487–7491 (2001).
  • Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C. A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep.3(7), 688–694 (2002).
  • Cheng HT, Miner JH, Lin M et al. γ-secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podocyte and proximal tubule formation in developing mouse kidney. Development130(20), 5031–5042 (2003).
  • Micchelli CA, Esler WP, Kimberly WT et al. γ-secretase/presenilin inhibitors for Alzheimer’s disease phenocopy Notch mutations in Drosophila. FASEB J.17(1), 79–81 (2003).
  • Searfoss GH, Jordan WH, Calligaro DO et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J. Biol. Chem.278(46), 46107–46116 (2003).
  • Milano J, McKay J, Dagenais C et al. Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol. Sci.82(1), 341–358 (2004).
  • Wong GT, Manfra D, Poulet FM et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem.279(13), 12876–12882 (2004).
  • Kopan R, Schroeter EH, Weintraub H, Nye JS. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc. Natl Acad. Sci. USA93(4), 1683–1688 (1996).
  • Talora C, Campese AF, Bellavia D et al. Notch signaling and diseases: an evolutionary journey from a simple beginning to complex outcomes. Biochim. Biophys. Acta1782(9), 489–497 (2008).
  • Lathia JD, Mattson MP, Cheng A. Notch: from neural development to neurological disorders. J. Neurochem.107(6), 1471–1481 (2008).
  • Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signalling – a structural and biochemical perspective. J. Cell Sci.121(Pt 19), 3109–3119 (2008).
  • Ilagan MX, Kopan R. SnapShot: notch signaling pathway. Cell128(6), 1246 (2007).
  • Parks AL, Curtis D. Presenilin diversifies its portfolio. Trends Genet.23(3), 140–150 (2007).
  • Beel AJ, Sanders CR. Substrate specificity of γ-secretase and other intramembrane proteases. Cell. Mol. Life Sci.65(9), 1311–1334 (2008).
  • Qian S, Jiang P, Guan XM et al. Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1–42/43 expression. Neuron20(3), 611–617 (1998).
  • Yu H, Saura CA, Choi SY et al. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron31(5), 713–726 (2001).
  • Saura CA, Choi SY, Beglopoulos V et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron42(1), 23–36 (2004).
  • Choi SH, Veeraraghavalu K, Lazarov O et al. Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron59(4), 568–580 (2008).
  • Niidome T, Taniuchi N, Akaike A, Kihara T, Sugimoto H. Differential regulation of neurogenesis in two neurogenic regions of APPswe/PS1dE9 transgenic mice. Neuroreport19(14), 1361–1364 (2008).
  • Rodriguez JJ, Jones VC, Tabuchi M et al. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS ONE3(8), e2935 (2008).
  • De Strooper B. Loss-of-function presenilin mutations in Alzheimer disease. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep.8(2), 141–146 (2007).
  • Wolfe MS. When loss is gain: reduced presenilin proteolytic function leads to increased Aβ42/Aβ40. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep.8(2), 136–140 (2007).
  • Shen J, Kelleher RJ 3rd. The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl Acad. Sci. USA104(2), 403–409 (2007).
  • Hong L, Koelsch G, Lin X et al. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science290(5489), 150–153 (2000).
  • Shimizu H, Tosaki A, Kaneko K et al. Crystal structure of an active form of BACE1, an enzyme responsible for amyloid β protein production. Mol. Cell Biol.28(11), 3663–3671 (2008).
  • Nguyen JT, Hamada Y, Kimura T, Kiso Y. Design of potent aspartic protease inhibitors to treat various diseases. Arch. Pharm. (Weinheim)341(9), 523–535 (2008).
  • Ghosh AK, Kumaragurubaran N, Hong L et al. Potent memapsin 2 (β-secretase) inhibitors: design, synthesis, protein-ligand x-ray structure, and in vivo evaluation. Bioorg. Med. Chem. Lett.18(3), 1031–1036 (2008).
  • Hamada Y, Ohta H, Miyamoto N et al. Novel non-peptidic and small-sized BACE1 inhibitors. Bioorg. Med. Chem. Lett.18(5), 1643–1647 (2008).
  • Hussain I, Hawkins J, Harrison D et al. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases β-cleavage of amyloid precursor protein and amyloid-β production in vivo. J. Neurochem.100(3), 802–809 (2007).
  • Cole DC, Stock JR, Chopra R et al. Acylguanidine inhibitors of β-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets. Bioorg. Med. Chem. Lett.18(3), 1063–1066 (2008).
  • Baxter EW, Conway KA, Kennis L et al. 2-amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (β-site APP cleaving enzyme): use of structure based design to convert a micromolar hit into a nanomolar lead. J. Med. Chem.50(18), 4261–4264 (2007).
  • van Es JH, van Gijn ME, Riccio O et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature435(7044), 959–963 (2005).
  • Fleisher AS, Raman R, Siemers ER et al. Phase II safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch. Neurol.65(8), 1031–1038 (2008).
  • Siemers ER, Dean RA, Friedrich S et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin. Neuropharmacol.30(6), 317–325 (2007).
  • Siemers ER, Quinn JF, Kaye J et al. Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology66(4), 602–604 (2006).
  • Siemers E, Skinner M, Dean RA et al. Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin. Neuropharmacol.28(3), 126–132 (2005).
  • in t’Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med.345(21), 1515–1521 (2001).
  • Aisen PS, Schafer KA, Grundman M et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA289(21), 2819–2826 (2003).
  • Martin BK, Szekely C, Brandt J et al. Cognitive function over time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch. Neurol.65(7), 896–905 (2008).
  • Weggen S, Eriksen JL, Das P et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature414(6860), 212–216 (2001).
  • Morihara T, Chu T, Ubeda O, Beech W, Cole GM. Selective inhibition of Aβ42 production by NSAID R-enantiomers. J. Neurochem.83(4), 1009–1012 (2002).
  • Eriksen JL, Sagi SA, Smith TE et al. NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. J. Clin. Invest.112(3), 440–449 (2003).
  • Takahashi Y, Hayashi I, Tominari Y et al. Sulindac sulfide is a noncompetitive γ-secretase inhibitor that preferentially reduces Aβ42 generation. J. Biol. Chem.278(20), 18664–18670 (2003).
  • Beher D, Clarke EE, Wrigley JD et al. Selected non-steroidal anti-inflammatory drugs and their derivatives target γ-secretase at a novel site. Evidence for an allosteric mechanism. J. Biol. Chem.279(42), 43419–43426 (2004).
  • Kukar T, Murphy MP, Eriksen JL et al. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nat. Med.11(5), 545–550 (2005).
  • Czech C, Burns MP, Vardanian L et al. Cholesterol independent effect of LXR agonist TO-901317 on γ-secretase. J. Neurochem.101(4), 929–936 (2007).
  • Kukar TL, Ladd TB, Bann MA et al. Substrate-targeting γ-secretase modulators. Nature453(7197), 925–929 (2008).
  • Narlawar R, Baumann K, Czech C, Schmidt B. Conversion of the LXR-agonist TO-901317 – from inverse to normal modulation of γ-secretase by addition of a carboxylic acid and a lipophilic anchor. Bioorg. Med. Chem. Lett.17(19), 5428–5431 (2007).
  • Kukar T, Prescott S, Eriksen JL et al. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci.8, 54 (2007).
  • Imbimbo BP, Del Giudice E, Colavito D et al. 1-(3’,4’-Dichloro-2-fluoro.1,1’-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel γ-secretase modulator, reduces brain β-amyloid pathology in a transgenic mouse model of Alzheimer’s disease without causing peripheral toxicity. J. Pharmacol. Exp. Ther.323(3), 822–830 (2007).
  • Page RM, Baumann K, Tomioka M et al. Generation of Aβ38 and Aβ42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and γ-secretase modulation. J. Biol. Chem.283(2), 677–683 (2008).
  • Barten DM, Guss VL, Corsa JA et al. Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J. Pharmacol. Exp. Ther.312(2), 635–643 (2005).
  • Tian G, Sobotka-Briner CD, Zysk J et al. Linear non-competitive inhibition of solubilized human γ-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines. J. Biol. Chem.277(35), 31499–31505 (2002).
  • Tian G, Ghanekar SV, Aharony D et al. The mechanism of γ-secretase: multiple inhibitor binding sites for transition state analogs and small molecule inhibitors. J. Biol. Chem.278(31), 28968–28975 (2003).
  • Clarke EE, Churcher I, Ellis S et al. Intra- or intercomplex binding to the γ-secretase enzyme. A model to differentiate inhibitor classes. J. Biol. Chem.281(42), 31279–31289 (2006).
  • Kreft A, Harrison B, Aschmies S et al. Discovery of a novel series of Notch-sparing γ-secretase inhibitors. Bioorg. Med. Chem. Lett.18(14), 4232–4236 (2008).
  • Mayer SC, Kreft AF, Harrison B et al. Discovery of begacestat, a Notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer’s disease. J. Med. Chem.51(23), 7348–7351 (2008).
  • Arbel M, Yacoby I, Solomon B. Inhibition of amyloid precursor protein processing by β-secretase through site-directed antibodies. Proc. Natl Acad. Sci. USA102(21), 7718–7723 (2005).
  • Paganetti P, Calanca V, Galli C, Stefani M, Molinari M. β-site specific intrabodies to decrease and prevent generation of Alzheimer’s Aβ peptide. J. Cell Biol.168(6), 863–868 (2005).
  • Chang WP, Downs D, Huang XP et al. Amyloid-β reduction by memapsin 2 (β-secretase) immunization. FASEB J.21(12), 3184–3196 (2007).
  • O’Connor T, Sadleir KR, Maus E et al. Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron60(6), 988–1009 (2008).
  • Faghihi MA, Modarresi F, Khalil AM et al. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of β-secretase. Nat. Med.14(7), 723–730 (2008).
  • Wang WX, Rajeev BW, Stromberg AJ et al. The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of β-site amyloid precursor protein-cleaving enzyme 1. J. Neurosci.28(5), 1213–1223 (2008).
  • Hebert SS, Horre K, Nicolai L et al. Loss of microRNA cluster miR-29a/β-1 in sporadic Alzheimer’s disease correlates with increased BACE1/β-secretase expression. Proc. Natl Acad. Sci. USA105(17), 6415–6420 (2008).
  • Boissonneault V, Plante I, Rivest S, Provost P. MicroRNA-298 and microRNA-328 regulate expression of mouse β-amyloid precursor protein-converting enzyme 1. J. Biol. Chem.284(4), 1971–1981 (2009).
  • Ratovitski T, Slunt HH, Thinakaran G et al. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J. Biol. Chem.272(39), 24536–24541 (1997).
  • Zhang J, Kang DE, Xia W et al. Subcellular distribution and turnover of presenilins in transfected cells. J. Biol. Chem.273(20), 12436–12442 (1998).
  • Thinakaran G, Harris CL, Ratovitski T et al. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem.272(45), 28415–28422 (1997).
  • Donoviel DB, Hadjantonakis AK, Ikeda M et al. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev.13(21), 2801–2810 (1999).
  • Lai MT, Chen E, Crouthamel MC et al. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping γ-secretase activities. J. Biol. Chem.278(25), 22475–22481 (2003).
  • Cheng H, Vetrivel KS, Gong P et al. Mechanisms of disease: new therapeutic strategies for Alzheimer’s disease – targeting APP processing in lipid rafts. Nat. Clin. Pract. Neurol.3(7), 374–382 (2007).
  • Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem.283(44), 29615–29619 (2008).
  • Tesco G, Koh YH, Kang EL et al. Depletion of GGA3 stabilizes BACE and enhances β-secretase activity. Neuron54(5), 721–737 (2007).
  • Sisodia SS, St George-Hyslop PH. γ-secretase, Notch, Aβ and Alzheimer’s disease: where do the presenilins fit in? Nat. Rev. Neurosci.3(4), 281–290 (2002).
  • Kaether C, Lammich S, Edbauer D et al. Presenilin-1 affects trafficking and processing of βAPP and is targeted in a complex with nicastrin to the plasma membrane. J. Cell Biol.158(3), 551–561 (2002).
  • Spasic D, Annaert W. Building γ-secretase: the bits and pieces. J. Cell Sci.121(Pt 4), 413–420 (2008).
  • Fukumori A, Okochi M, Tagami S et al. Presenilin-dependent γ-secretase on plasma membrane and endosomes is functionally distinct. Biochemistry45(15), 4907–4914 (2006).
  • Thathiah A, Spittaels K, Hoffmann M et al. The orphan G protein-coupled receptor 3 modulates amyloid-β peptide generation in neurons. Science323(5916), 946–951 (2009).
  • Ehehalt R, Keller P, Haass C, Thiele C, Simons K. Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts. J. Cell Biol.160(1), 113–123 (2003).
  • Simons K, Toomre D. Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol.1(1), 31–39 (2000).
  • Helms JB, Zurzolo C. Lipids as targeting signals: lipid rafts and intracellular trafficking. Traffic5(4), 247–254 (2004).
  • Sakurai T, Kaneko K, Okuno M et al. Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing. J. Cell Biol.183(2), 339–352 (2008).
  • Postina R, Schroeder A, Dewachter I et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest.113(10), 1456–1464 (2004).
  • Marcade M, Bourdin J, Loiseau N et al. Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J. Neurochem.106(1), 392–404 (2008).
  • Sastre M, Steiner H, Fuchs K et al. Presenilin-dependent γ-secretase processing of β-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep.2(9), 835–841 (2001).
  • Gu Y, Misonou H, Sato T et al. Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling γ-secretase-like cleavage of Notch. J. Biol. Chem.276(38), 35235–35238 (2001).
  • Yu C, Kim SH, Ikeuchi T et al. Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment γ. Evidence for distinct mechanisms involved in γ-secretase processing of the APP and Notch1 transmembrane domains. J. Biol. Chem.276(47), 43756–43760 (2001).
  • Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the β-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J. Biol. Chem.276(43), 40288–40292 (2001).
  • Okochi M, Steiner H, Fukumori A et al. Presenilins mediate a dual intramembranous γ-secretase cleavage of Notch-1. EMBO J.21(20), 5408–5416 (2002).
  • Zhao G, Cui MZ, Mao G et al. γ-cleavage is dependent on ζ-cleavage during the proteolytic processing of amyloid precursor protein within its transmembrane domain. J. Biol. Chem.280(45), 37689–37697 (2005).
  • Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y et al. Longer forms of amyloid β protein: implications for the mechanism of intramembrane cleavage by γ-secretase. J. Neurosci.25(2), 436–445 (2005).
  • Sato T, Nyborg AC, Iwata N et al. Signal peptide peptidase: biochemical properties and modulation by nonsteroidal antiinflammatory drugs. Biochemistry45(28), 8649–8656 (2006).
  • Fluhrer R, Grammer G, Israel L et al. A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2b. Nat. Cell Biol.8(8), 894–896 (2006).
  • Fluhrer R, Fukumori A, Martin L et al. Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. J. Biol. Chem.283(44), 30121–30128 (2008).
  • Sato T, Ananda K, Cheng CI et al. Distinct pharmacological effects of inhibitors of signal peptide peptidase and γ-secretase. J. Biol. Chem.283(48), 33287–33295 (2008).
  • Hemming ML, Elias JE, Gygi SP, Selkoe DJ. Proteomic profiling of γ-secretase substrates and mapping of substrate requirements. PLoS Biol.6(10), e257 (2008).
  • Lemberg MK, Martoglio B. Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol. Cell10(4), 735–744 (2002).
  • Martin L, Fluhrer R, Haass C. Substrate Requirements for SPPL2β-dependent regulated intramembrane proteolysis. J. Biol. Chem.284(9), 5662–5670 (2009).
  • Munter LM, Voigt P, Harmeier A et al. GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Aβ42. EMBO J.26(6), 1702–1712 (2007).
  • Kienlen-Campard P, Tasiaux B, Van Hees J et al. Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs. J. Biol. Chem.283(12), 7733–7744 (2008).
  • Sato T, Tang TC, Reubins G et al. A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis. Proc. Natl Acad. Sci. USA106(5), 1421–1426 (2009).
  • Urban S, Freeman M. Substrate specificity of rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain. Mol. Cell11(6), 1425–1434 (2003).
  • Ye J, Dave UP, Grishin NV, Goldstein JL, Brown MS. Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease. Proc. Natl Acad. Sci. USA97(10), 5123–5128 (2000).
  • Urban S, Wolfe MS. Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc. Natl Acad. Sci. USA102(6), 1883–1888 (2005).
  • Tomita T, Chang TY, Kodama T, Iwatsubo T. βAPP γ-secretase and SREBP site 2 protease are two different enzymes. Neuroreport9(5), 911–913 (1998).
  • Annaert WG, Esselens C, Baert V et al. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron32(4), 579–589 (2001).
  • Tomita T, Takikawa R, Koyama A et al. C terminus of presenilin is required for overproduction of amyloidogenic Aβ42 through stabilization and endoproteolysis of presenilin. J. Neurosci.19(24), 10627–10634 (1999).
  • Kaether C, Capell A, Edbauer D et al. The presenilin C-terminus is required for ER-retention, nicastrin-binding and γ-secretase activity. EMBO J.23(24), 4738–4748 (2004).
  • Bergman A, Laudon H, Winblad B, Lundkvist J, Naslund J. The extreme C terminus of presenilin 1 is essential for γ-secretase complex assembly and activity. J. Biol. Chem.279(44), 45564–45572 (2004).
  • Futai E, Yagishita S, Ishiura S. Nicastrin is dispensable for γ-secretase protease activity in the presence of specific presenilin mutations. J. Biol. Chem. DOI: 10.1074/jbc.M807653200 (2009) (Epub ahead of print).
  • Das C, Berezovska O, Diehl TS et al. Designed helical peptides inhibit an intramembrane protease. J. Am. Chem. Soc.125(39), 11794–11795 (2003).
  • Kornilova AY, Bihel F, Das C, Wolfe MS. The initial substrate-binding site of γ-secretase is located on presenilin near the active site. Proc. Natl Acad. Sci. USA102(9), 3230–3235 (2005).
  • Morohashi Y, Kan T, Tominari Y et al. C-terminal fragment of presenilin is the molecular target of a dipeptidic γ-secretase-specific inhibitor DAPT (N-.N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester). J. Biol. Chem.281(21), 14670–14676 (2006).
  • Fuwa H, Takahashi Y, Konno Y et al. Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic γ-secretase inhibitors. ACS Chem. Biol.2(6), 408–418 (2007).
  • Kornilova AY, Das C, Wolfe MS. Differential effects of inhibitors on the γ-secretase complex. Mechanistic implications. J. Biol. Chem.278(19), 16470–16473 (2003).
  • Weihofen A, Lemberg MK, Friedmann E et al. Targeting presenilin-type aspartic protease signal peptide peptidase with γ-secretase inhibitors. J. Biol. Chem.278(19), 16528–16533 (2003).
  • Nyborg AC, Jansen K, Ladd TB, Fauq A, Golde TE. A signal peptide peptidase (SPP) reporter activity assay based on the cleavage of type II membrane protein substrates provides further evidence for an inverted orientation of the SPP active site relative to presenilin. J. Biol. Chem.279(41), 43148–43156 (2004).
  • Lemberg MK, Bland FA, Weihofen A, Braud VM, Martoglio B. Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes. J. Immunol.167(11), 6441–6446 (2001).
  • McLauchlan J, Lemberg MK, Hope G, Martoglio B. Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J.21(15), 3980–3988 (2002).
  • Nyborg AC, Ladd TB, Jansen K, Kukar T, Golde TE. Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase. FASEB J.20(10), 1671–1679 (2006).
  • Friedmann E, Hauben E, Maylandt K et al. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production. Nat. Cell Biol.8(8), 843–848 (2006).
  • Grigorenko AP, Moliaka YK, Soto MC, Mello CC, Rogaev EI. The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins. Proc. Natl Acad. Sci. USA101(41), 14955–14960 (2004).
  • Casso DJ, Tanda S, Biehs B, Martoglio B, Kornberg TB. Drosophila signal peptide peptidase is an essential protease for larval development. Genetics170(1), 139–148 (2005).
  • Zhao B, Yu M, Neitzel M et al. Identification of γ-secretase inhibitor potency determinants on presenilin. J. Biol. Chem.283(5), 2927–2938 (2008).
  • Fuwa H, Hiromoto K, Takahashi Y et al. Synthesis of biotinylated photoaffinity probes based on arylsulfonamide γ-secretase inhibitors. Bioorg. Med. Chem. Lett.16(16), 4184–4189 (2006).
  • Hung LW, Ciccotosto GD, Giannakis E et al. Amyloid-β peptide (Aβ) neurotoxicity is modulated by the rate of peptide aggregation: Aβ dimers and trimers correlate with neurotoxicity. J. Neurosci.28(46), 11950–11958 (2008).
  • Espeseth AS, Xu M, Huang Q et al. Compounds that bind APP and inhibit Aβ processing in vitro suggest a novel approach to Alzheimer disease therapeutics. J. Biol. Chem.280(18), 17792–17797 (2005).
  • Lleo A, Berezovska O, Herl L et al. Nonsteroidal anti-inflammatory drugs lower Aβ42 and change presenilin 1 conformation. Nat. Med.10(10), 1065–1066 (2004).
  • Karlin A, Akabas MH. Substituted-cysteine accessibility method. Methods Enzymol.293, 123–145 (1998).
  • Seal RP, Leighton BH, Amara SG. Transmembrane topology mapping using biotin-containing sulfhydryl reagents. Methods Enzymol.296, 318–331 (1998).
  • Sato C, Morohashi Y, Tomita T, Iwatsubo T. Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. J. Neurosci.26(46), 12081–12088 (2006).
  • Tolia A, Chavez-Gutierrez L, De Strooper B. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the γ-secretase complex. J. Biol. Chem.281(37), 27633–27642 (2006).
  • Sato C, Takagi S, Tomita T, Iwatsubo T. The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the γ-secretase. J. Neurosci.28(24), 6264–6271 (2008).
  • Tolia A, Horre K, De Strooper B. Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of γ-secretase. J. Biol. Chem.283(28), 19793–19803 (2008).
  • Lazarov VK, Fraering PC, Ye W et al. Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores. Proc. Natl Acad. Sci. USA103(18), 6889–6894 (2006).
  • Osenkowski P, Li H, Ye W et al. Cryoelectron microscopy structure of purified γ-secretase at 12 A resolution. J. Mol. Biol.385(2), 642–652 (2009).
  • Urban S, Shi Y. Core principles of intramembrane proteolysis: comparison of rhomboid and site-2 family proteases. Curr. Opin. Struct. Biol.18(4), 432–441 (2008).
  • Koch U, Radtke F. Notch and cancer: a double-edged sword. Cell. Mol. Life Sci.64(21), 2746–2762 (2007).
  • Rizzo P, Osipo C, Foreman K et al. Rational targeting of Notch signaling in cancer. Oncogene27(38), 5124–5131 (2008).
  • Yan M, Plowman GD. Delta-like 4/Notch signaling and its therapeutic implications. Clin. Cancer Res.13(24), 7243–7246 (2007).
  • Ischenko I, Seeliger H, Schaffer M, Jauch KW, Bruns CJ. Cancer stem cells: how can we target them? Curr. Med. Chem.15(30), 3171–3184 (2008).
  • Wang Z, Li Y, Banerjee S, Sarkar FH. Emerging role of Notch in stem cells and cancer. Cancer Lett. DOI: 10.1016/j.canlet.2008.09.030 (2008) (Epub ahead of print).
  • Real PJ, Tosello V, Palomero T et al. γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med.15(1), 50–58 (2009).
  • Reiss K, Saftig P. The ‘a disintegrin and metalloprotease’ (ADAM) family of sheddases: physiological and cellular functions. Semin. Cell Dev. Biol.20(2), 126–137 (2009).
  • Parsons RB, Austen BM. Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer’s disease. Biochem. Soc. Trans.35(Pt 5), 974–979 (2007).

Patents

  • PERSEUS PROTEOMICS INC.: WO2007129457 (2007)
  • VLAAMS INTERUNIVERSITAIR INSTITUUT VOOR BIOTECHNOLOGIE VZW: WO2004026331 (2004)

Website

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:

Order Reprints Request Corporate Permissions

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:

Request Academic Permissions

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.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.