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CNS Drugs

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01-05-2006 | Leading Article

Inhibition of γ-Secretase as a Therapeutic Intervention for Alzheimer’s Disease

Prospects, Limitations and Strategies

Authors: Dr Geneviève Evin, Marijke Fleur Sernee, Colin L. Masters

Published in: CNS Drugs | Issue 5/2006

Abstract

Genetic and experimental evidence points to amyloid-β (Aβ) peptide as the culprit in Alzheimer’s disease pathogenesis. This protein fragment abnormally accumulates in the brain cortex and hippocampus of patients with Alzheimer’s disease, and self-aggregates to form toxic oligomers causing neurodegeneration.

Aβ is heterogeneous and produced from a precursor protein (amyloid precursor protein [APP]) by two sequential proteolytic cleavages that involve β- and γ-secretases. This latter enzyme represents a potentially attractive drug target since it dictates the solubility of the generated Aβ fragment by creating peptides of various lengths, namely Aβ₄₀ and Aβ₄₂, the longest being the most aggregating. γ-Secretase comprises a molecular complex of four integral membrane proteins — presenilin,nicastrin, APH-1 and PEN-2 — and its molecular mechanism remains under extensive scrutiny. The ratio of Aβ₄₂ over Aβ₄₀ is increased by familial Alzheimer’s disease mutations occurring in the presenilin genes or in APP, near the γ-secretase cleavage site.

Potent γ-secretase inhibitors have been identified by screening drug libraries or by designing aspartyl protease transition-state analogues based on the APP substrate cleavage site. Most of these compounds are not specific for γ-secretase cleavage of APP, and equally inhibit the processing of other γ-secretase substrates, such as Notch and a subset of cell-surface receptors and proteins involved in embryonic development, haematopoiesis, cell adhesion and cell/cell contacts. Therefore, current research aims at finding compounds that show selectivity for APP cleavage, and particularly that inhibit the formation of the aggregating form, Aβy₄₂. Compounds that target the substrate docking site rather than the enzyme active site are also being investigated as an alternative strategy. The finding that some NSAID analogues preferentially inhibit the formation of Aβ₄₂ over Aβ₄₀ and do not affect Notch processing has opened a new therapeutic window. The progress in design of selective inhibitors as well as recent results obtained in animal studies prove that γ-secretase remains among the best targets for the therapeutic control of amyloid build-up in Alzheimer’s disease. The full understanding of γ-secretase regulation may yet uncover new therapeutic leads.

Bertram L, Tanzi RE. Dancing in the dark? The status of late-onset Alzheimer’s disease genetics. J Mol Neurosci 2001; 17(2): 127–36PubMedCrossRef

Voisin T, Reynish E, Portet F, et al. What are the treatment options for patients with severe Alzheimer’s disease? CNS Drugs 2004; 18(9): 575–83PubMedCrossRef

Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120(3): 885–90PubMedCrossRef

Masters CL, Simms G, Weinman NA, et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985; 82(12): 4245–9PubMedCrossRef

Kang J, Lemaire HG, Unterbeck A, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987; 325(6106): 733–6PubMedCrossRef

Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001; 81(2): 741–66PubMed

Evin G, Weidemann A. Biogenesis and metabolism of Alzheimer’s disease Aβ amyloid peptides. Peptides 2002; 23(7): 1285–97PubMedCrossRef

Sisodia SS, Koo EH, Beyreuther K, et al. Evidence that β-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 1990; 248(4954): 492–5PubMedCrossRef

Hardy J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 1997; 20(4): 154–9PubMedCrossRef

10.

St George-Hyslop PH. Genetic factors in the genesis of Alzheimer’s disease. Ann N Y Acad Sci 2000; 924: 1–7PubMedCrossRef

11.

Bertram L, McQueen M, Mullin K, et al. The AlzGene database: Alzheimer research forum [online]. Available from URL: http://www.alzforum.org/res/com/mut/pre/default.asp [Accessed 24/3/06]

12.

Holsinger RM, McLean CA, Beyreuther K, et al. Increased expression of the amyloid precursor β-secretase in Alzheimer’s disease. Ann Neurol 2002; 51(6): 783–6PubMedCrossRef

13.

Fukumoto H, Cheung BS, Hyman BT, et al. β-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002; 59(9): 1381–9PubMedCrossRef

14.

Yang LB, Lindholm K, Yan R, et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003; 9(1): 3–4PubMedCrossRef

15.

McLean CA, Cherny RA, Fraser FW, et al. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 1999; 46(6): 860–6PubMedCrossRef

16.

Nunan J, Shearman MS, Checler F, et al. The C-terminal fragment of the Alzheimer’s disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from γ-secretase. Eur J Biochem 2001; 268(20): 5329–36PubMedCrossRef

17.

Weidemann A, Eggert S, Reinhard FB, et al. A novel ε-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 2002; 41(8): 2825–35PubMedCrossRef

18.

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 2001; 2(9): 835–41PubMedCrossRef

19.

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 Notchl transmembrane domains. J Biol Chem 2001; 276(47): 43756–60PubMedCrossRef

20.

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 2001; 276(38): 35235–8PubMedCrossRef

21.

Cao X, Sudhof TC. Dissection of amyloid-β precursor protein-dependent transcriptional transactivation. J Biol Chem 2004; 279(23): 24601–11PubMedCrossRef

22.

Buxbaum JD, Liu KN, Luo Y, et al. Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 1998; 273(43): 27765–7PubMedCrossRef

23.

Lammich S, Kojro E, Postina R, et al. Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A 1999; 96: 3922–7PubMedCrossRef

24.

Asai M, Hattori C, Szabo B, et al. Putative function of ADAM9, ADAM10, and ADAM17 as APP α-secretase. Biochem Biophys Res Commun 2003; 301(1): 231–5PubMedCrossRef

25.

Vassar R, Bennett BD, Babu-Khan S, et al. β-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286(5440): 735–41PubMedCrossRef

26.

Hussain I, Powell D, Howlett DR, et al. Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase. Mol Cell Neurosci 1999; 14(6): 419–27PubMedCrossRef

27.

Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 1999; 402(6761): 537–40PubMedCrossRef

28.

Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature 1999; 402(6761): 533–7PubMedCrossRef

29.

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 U S A 2000; 97: 1456–60PubMedCrossRef

30.

Cai H, Wang Y, McCarthy D, et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci 2001 Mar; 4(3): 233–4PubMedCrossRef

31.

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 2001 Mar; 4(3): 231–2PubMedCrossRef

32.

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 2001; 10: 1317–24PubMedCrossRef

33.

Lichtenthaler S, Wang R, Grimm H, et al. Mechanism of the cleavage specificity of Alzheimer’s disease γ-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc Natl Acad Sci U S A 1999; 96: 3053–8PubMedCrossRef

34.

Wang R, Sweeney D, Gandy SE, et al. The profile of soluble amyloid β protein in cultured cell media: detection and quantification of amyloid β protein and variants by immunoprecipitation-mass spectrometry. J Biol Chem 1996; 271(50): 31894–902PubMedCrossRef

35.

Golde TE, Eckman CB, Younkin SG. Biochemical detection of Aβ isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer’s disease. Biochem Biophys Acta 2000; 1502: 172–87PubMedCrossRef

36.

Murphy MP, Hickman LJ, Eckman CB, et al. γ-Secretase, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid β peptides of varying length. J Biol Chem 1999; 274(17): 11914–23PubMedCrossRef

37.

Beher D, Wrigley JD, Owens AP, et al. Generation of C-terminally truncated amyloid-β peptides is dependent on γ-secretase activity. J Neurochem 2002; 82(3): 563–75PubMedCrossRef

38.

Esh C, Patton L, Kalback W, et al. Altered APP processing in PDAPP (Val717→Phe) transgenic mice yields extended-length Aβ peptides. Biochemistry 2005 Oct 25; 44(42): 13807–19PubMedCrossRef

39.

Jarrett JT, Lansbury Jr PT. Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 1993; 73(6): 1055–8PubMedCrossRef

40.

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 2005 Jan 12; 25(2): 436–45PubMedCrossRef

41.

Zhao G, Mao G, Tan J, et al. Identification of a new presenilin-dependent zeta-cleavage site within the transmembrane domain of amyloid precursor protein. J Biol Chem 2004 Dec 3; 279(49): 50647–50PubMedCrossRef

42.

Zhao G, Cui MZ, Mao G, et al. γ-Cleavage is dependent on zeta-cleavage during the proteolytic processing of amyloid precursor protein within its transmembrane domain. J Biol Chem 2005 Nov 11; 280(45): 37689–97PubMedCrossRef

43.

Sato T, Tanimura Y, Hirotani N, et al. Blocking the cleavage at midportion between γ- and ε-sites remarkably suppresses the generation of amyloid β-protein. FEBS Lett 2005 May 23; 579(13): 2907–12PubMedCrossRef

44.

Funamoto S, Morishima-Kawashima M, Tanimura Y, et al. Truncated carboxyl-terminal fragments of β-amyloid precursor protein are processed to amyloid β-proteins 40 and 42. Biochemistry 2004 Oct 26; 43(42): 13532–40PubMedCrossRef

45.

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 U S A 2000; 97(11): 6138–43PubMedCrossRef

46.

Shearman MS, Beher D, Clarke EE, et al. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid β-protein precursor γ-secretase activity. Biochemistry 2000; 39(30): 8698–704PubMedCrossRef

47.

Wolfe MS, Citron M, Diehl TS, et al. A substrate-based difluoro ketone selectively inhibits Alzheimer’s γ-secretase activity. J Med Chem 1998; 41(1): 6–9PubMedCrossRef

48.

Tian G, Sobotka-Briner CD, Zysk J, et al. Linear non-competitive inhibition of solubilized human γ-secretase by pepstatin A methylester, L-685458, sulfonamides and benzodiazepines. J Biol Chem 2002; 277(35): 31499–505PubMedCrossRef

49.

De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391(6665): 387–90PubMedCrossRef

50.

Herreman A, Serneels L, Annaert W, et al. Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2000; 2(7): 461–2PubMedCrossRef

51.

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 2000; 2(7): 463–5PubMedCrossRef

52.

Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995; 375(6534): 754–60PubMedCrossRef

53.

Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995; 269(5226): 973–7PubMedCrossRef

54.

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. Nature 1995; 376(6543): 775–8PubMedCrossRef

55.

De Strooper B, Beullens M, Contreras B, et al. Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer’s disease-associated presenilins. J Biol Chem 1997 Feb 7; 272(6): 3590–8PubMedCrossRef

56.

Doan A, Thinakaran G, Borchelt DR, et al. Protein topology of presenilin1. Neuron 1996 Nov; 17(5): 1023–30PubMedCrossRef

57.

Li X, Greenwald I. Membrane topology of the C. elegans SEL-12 presenilin. Neuron 1996 Nov; 17(5): 1015–21PubMedCrossRef

58.

Lehmann S, Chiesa R, Harris DA. Evidence for a six-transmembrane domain structure of presenilin1. J Biol Chem 1997 May 2; 272(18): 12047–51PubMedCrossRef

59.

Nakai T, Yamasaki A, Sakaguchi M, et al. Membrane topology of Alzheimer’s disease-related presenilin 1: evidence for the existence of a molecular species with a seven membrane-spanning and one membrane-embedded structure. J Biol Chem 1999 Aug 13; 274(33): 23647–58PubMedCrossRef

60.

Li X, Greenwald I. Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc Natl Acad Sci U S A 1998 Jun 9; 95(12): 7109–14PubMedCrossRef

61.

Thinakaran G, Borchelt DR, Lee MK, et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996; 17(1): 181–90PubMedCrossRef

62.

Henricson A, Kall L, Sonnhammer EL. A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence. FEBS J 2005 Jun; 272(11): 2727–33PubMedCrossRef

63.

Oh YS, Turner RJ. Topology of the C-terminal fragment of human presenilin1. Biochemistry 2005 Sep 6; 44(35): 11821–8PubMedCrossRef

64.

Laudon H, Hansson EM, Melen K, et al. A nine-transmembrane domain topology for presenilin1. J Biol Chem 2005 Oct 21; 280(42): 35352–60PubMedCrossRef

65.

Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid b-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996; 2(8): 864–70PubMedCrossRef

66.

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 1997; 3(1): 67–72PubMedCrossRef

67.

Weidemann A, Paliga K, Durrwang U, et al. Formation of stable complexes between two Alzheimer’s disease gene products: presenilin-2 and β-amyloid precursor protein. Nat Med 1997 Mar; 3(3): 328–32PubMedCrossRef

68.

Xia W, Ray WJ, Ostaszewski BL, et al. Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid β-protein generation. Proc Natl Acad Sci U S A 2000; 97(16): 9299–304PubMedCrossRef

69.

Wolfe MS, Xia W, Ostaszewski BL, et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 1999; 398(6727): 513–7PubMedCrossRef

70.

Wolfe MS, Xia W, Moore CL, et al. Peptidomimetic probes and molecular modeling suggest that Alzheimer’s γ-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 1999; 38: 4720–7PubMedCrossRef

71.

Li YM, Xu M, Lai MT, et al. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin1. Nature 2000; 405(6787): 689–94PubMedCrossRef

72.

Esler WP, Kimberly WT, Ostaszewski BL, et al. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat Cell Biol 2000; 2(7): 428–34PubMedCrossRef

73.

Seiffert D, Bradley JD, Rominger CM, et al. Presenilin-1 and -2 are molecular targets for γ-secretase inhibitors. J Biol Chem 2000; 275(44): 34086–91PubMedCrossRef

74.

Evin G, Sharpies RA, Weidemann A, et al. Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer’s disease. Biochemistry 2001; 40(28): 8359–68PubMedCrossRef

75.

LaPointe CF, Taylor RK. The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases. J Biol Chem 2000; 275(2): 1502–10CrossRef

76.

Steiner H, Kostka M, Romig H, et al. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nat Cell Biol 2000; 2(11): 848–51PubMedCrossRef

77.

Weihofen A, Binns K, Lemberg MK, et al. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 2002; 296(5576): 2215–8PubMedCrossRef

78.

McCarthy JV. Involvement of presenilins in cell-survival signalling pathways. Biochem Soc Trans 2005 Aug; 33 (Pt 4): 568–72PubMedCrossRef

79.

Kang DE, Soriano S, Xia X, et al. Presenilin couples the paired phosphorylation of β-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell 2002 Sep 20; 110(6): 751–62PubMedCrossRef

80.

Esselens C, Oorschot V, Baert V, et al. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol 2004 Sep 27; 166(7): 1041–54PubMedCrossRef

81.

Yu G, Chen F, Levesque G, et al. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains β-catenin. J Biol Chem 1998; 273(26): 16470–5PubMedCrossRef

82.

Yu G, Nishimura M, Arawaka S, et al. Nicastrin modulates presenilin-mediated Notch/GLP-1 signal transduction and βAPP processing. Nature 2000; 407(6800): 48–54PubMedCrossRef

83.

Leem JY, Vijayan S, Han P, et al. Presenilin 1 is required for maturation and cell surface accumulation of nicastrin. J Biol Chem 2002; 277(21): 19236–40PubMedCrossRef

84.

Edbauer D, Winkler E, Haass C, et al. Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation. Proc Natl Acad Sci U S A 2002; 99(13): 8666–71PubMed

85.

Kimberly WT, LaVoie MJ, Ostaszewski BL, et al. Complex N-linked glycosylated Nicastrin associates with active γ-secretase and undergoes tight cellular regulation. J Biol Chem 2002; 277(38): 35113–7PubMedCrossRef

86.

Yang DS, Tandon A, Chen F, et al. Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. J Biol Chem 2002; 277(31): 28135–42PubMedCrossRef

87.

Li T, Ma G, Cai H, et al. 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 2003 Apr 15; 23(8): 3272–7PubMed

88.

Shah S, Lee SF, Tabuchi K, et al. Nicastrin functions as a γ-secretase-substrate receptor. Cell 2005 Aug 12; 122(3): 435–47PubMedCrossRef

89.

Wong PC, Zheng H, Chen H, et al. Presenilin 1 is required for Notchl and DII1 expression in the paraxial mesoderm. Nature 1997; 387(6630): 288–92PubMedCrossRef

90.

Hartmann D, Tournoy J, Saftig P, et al. Implication of APP secretases in Notch signalling. J Mol Neurosci 2001 Oct; 17(2): 171 -181PubMedCrossRef

91.

Lai EC. Notch signaling: control of cell communication and cell fate. Development 2004; 131(5): 965–73PubMedCrossRef

92.

Logeat F, Bessia C, Brou C, et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A 1998 Jul 7; 95(14): 8108–12PubMedCrossRef

93.

Kopan R, Schroeter EH, Weintraub H, et al. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci U S A 1996; 93(4): 1683–8PubMedCrossRef

94.

Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 2000; 5(2): 207–16PubMedCrossRef

95.

De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 1999 Apr 8; 398(6727): 518–22PubMedCrossRef

96.

Okochi M, Steiner H, Fukumori A, et al. Presenilins mediate a dual intramembranous γ-secretase cleavage of Notch-1. EMBO J 2002 Oct 15; 21(20): 5408–16PubMedCrossRef

97.

Mizutani T, Taniguchi Y, Aoki T, et al. Conservation of the biochemical mechanisms of signal transduction among mammalian Notch family members. Proc Natl Acad Sci U S A 2001; 98(16): 9026–31PubMedCrossRef

98.

Baumeister R, Leimer U, Zweckbronner I, et al. Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1997; 1(2): 149–59PubMedCrossRef

99.

Guo Y, Livne-Bar I, Zhou L, et al. Drosophila presenilin is required for neuronal differentiation and affects Notch subcellular localization and signaling. J Neurosci 1999; 19(19): 8435–42PubMed

100.

Wittenburg N, Eimer S, Lakowski B, et al. Presenilin is required for proper morphology and function of neurons in C. elegans. Nature 2000; 406(6793): 306–9PubMedCrossRef

101.

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 Cell 2002; 3(1): 85–97PubMedCrossRef

102.

Goutte C, Tsunozaki M, Hale VA, et al. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 2002; 99(2): 775–9PubMedCrossRef

103.

Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the γ-secretase complex. Nature 2003; 422(6930): 438–41PubMedCrossRef

104.

Edbauer D, Winkler E, Regula JT, et al. Reconstitution of γ-secretase activity. Nat Cell Biol 2003; 5(5): 486–8PubMedCrossRef

105.

Hayashi I, Urano Y, Fukuda R, et al. Selective reconstitution and recovery of functional γ-secretase complex on budded baculovirus particles. J Biol Chem 2004; 279(36): 38040–6PubMedCrossRef

106.

Steiner H, Winkler E, Edbauer D, et al. PEN-2 is an integral component of the γ-secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem 2002; 277(42): 39062–5PubMedCrossRef

107.

Lee SF, Shah S, Li H, et al. Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-β precursor protein and Notch. J Biol Chem 2002; 277(47): 45013–9PubMedCrossRef

108.

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 2003; 278(39): 37213–22CrossRef

109.

Hu Y, Fortini ME. Different cofactor activities in γ-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex. J Cell Biol 2003; 161(4): 685–90PubMedCrossRef

110.

Gu Y, Chen F, Sanjo N, et al. 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(9): 7374–80PubMedCrossRef

111.

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 2005 Apr 1; 280(13): 12967–75PubMedCrossRef

112.

Capell A, Beher D, Prokop S, et al. γ-Secretase complex assembly within the early secretory pathway. J Biol Chem 2005 Feb 25; 280(8): 6471–8PubMedCrossRef

113.

Shirotani K, Edbauer D, Prokop S, et al. Identification of distinct γ-secretase complexes with different APH-1 variants. J Biol Chem 2004 Oct 1; 279(40): 41340–5PubMedCrossRef

114.

Ma G, Li T, Price DL, et al. APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. J Neurosci 2005 Jan 5; 25(1): 192–8PubMedCrossRef

115.

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 U S A 2005 Feb 1; 102(5): 1719–24PubMedCrossRef

116.

Culvenor JG, Ilaya NT, Ryan MT, et al. Characterization of presenilin complexes from mouse and human brain using blue native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations. Eur J Biochem 2004; 271(2): 375–85PubMedCrossRef

117.

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 U S A 2003; 100(11): 6382–7PubMedCrossRef

118.

Farmery MR, Tjernberg LO, Pursglove SE, et al. Partial purification and characterization of γ-secretase from post-mortem human brain. J Biol Chem 2003; 278(27): 24277–84PubMedCrossRef

119.

Esler WP, Kimberly WT, Ostaszewski BL, et al. Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a γ substrate. Proc Natl Acad Sci U S A 2002 Mar 5; 99(5): 2720–5PubMedCrossRef

120.

Fraering PC, LaVoie MJ, Ye W, et al. Detergent-dependent dissociation of active γ-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. Biochemistry 2004; 43(2): 323–33PubMedCrossRef

121.

Fraering PC, Ye W, Strub JM, et al. Purification and characterization of the human γ-secretase complex. Biochemistry 2004; 43(30): 9774–89PubMedCrossRef

122.

Beher D, Fricker M, Nadin A, et al. In vitro characterization of the presenilin-dependent γ-secretase complex using a novel affinity ligand. Biochemistry 2003; 42(27): 8133–42PubMedCrossRef

123.

Gu Y, Sanjo N, Chen F, et al. The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities. J Biol Chem 2004; 279(30): 31329–36PubMedCrossRef

124.

Evin G, Canterford LD, Hoke DE, et al. Transition-state analogue γ-secretase inhibitors stabilize a 900 kDa presenilin/nicastrin complex. Biochemistry 2005 Mar 22; 44(11): 4332–41PubMedCrossRef

125.

Hoke DE, Tan JL, Ilaya NT, et al. In vitro γ-secretase cleavage of the Alzheimer’s amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc. FEBS J 2005; 272(21): 5544–57PubMedCrossRef

126.

Berezovska O, Ramdya P, Skoch J, et al. Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin 1-γ-secretase complex in cells demonstrated by fluorescence lifetime imaging. J Neurosci 2003; 23(11): 4560–6PubMed

127.

Ramdya P, Skoch J, Bacskai BJ, et al. Activated Notch1 associates with a presenilin-1/γ-secretase docking site. J Neurochem 2003; 87(4): 843–50PubMedCrossRef

128.

Kornilova AY, Das C, Wolfe MS. Differential effects of inhibitors on the γ-secretase complex. Mechanistic implications. J Biol Chem 2003; 278(19): 16470–3

129.

Saura CA, Tomita T, Davenport F, et al. Evidence that intramolecular associations between presenilin domains are obligatory for endoproteolytic processing. J Biol Chem 1999 May 14; 274(20): 13818–23PubMedCrossRef

130.

Chen F, Tandon A, Sanjo N, et al. Presenilin 1 and presenilin 2 have differential effects on the stability and maturation of nicastrin in mammalian brain. J Biol Chem 2003 May 30; 278(22): 19974–9PubMedCrossRef

131.

Lai MT, Chen E, Crouthamel MC, et al. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping γ-secretase activities. J Biol Chem 2003 Jun 20; 278(25): 22475–81PubMedCrossRef

132.

Mastrangelo P, Mathews PM, Chishti MA, et al. Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases. Proc Natl Acad Sci U S A 2005 Jun 21; 102(25): 8972–7PubMedCrossRef

133.

Wilson CA, Doms RW, Zheng H, et al. Presenilins are not required for Aβ42 production in the early secretory pathway. Nat Neurosci 2002; 5(9): 849–55PubMedCrossRef

134.

Armogida M, Petit A, Vincent B, et al. Endogenous β-amyloid production in presenilin-deficient embryonic mouse fibroblasts. Nat Cell Biol 2001; 3(11): 1030–3PubMedCrossRef

135.

Selkoe D, Kopan R. Notch and presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 2003; 26: 565–97PubMedCrossRef

136.

Leissring MA, Murphy MP, Mead TR, et al. A physiologic signaling role for the γ-secretase-derived intracellular fragment of APP. Proc Natl Acad Sci U S A 2002; 99(7): 4697–702PubMedCrossRef

137.

von Rotz RC, Kohli BM, Bosset J, et al. The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J Cell Sci 2004; 117 (Pt 19): 4435–48CrossRef

138.

Fortini ME. γ-Secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol 2002; 3(9): 673–84PubMedCrossRef

139.

Eggert S, Paliga K, Soba P, et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α-, β-, γ-, and ε-like cleavages: modulation of APLP-1 processing by N-glycosylation. J Biol Chem 2004; 279(18): 18146–56PubMedCrossRef

140.

Walsh DM, Fadeeva JV, LaVoie MJ, et al. γ-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins. Biochemistry 2003; 42(22): 6664–73PubMedCrossRef

141.

Kopan R, Goate A. A common enzyme connects Notch signaling and Alzheimer’s disease. Genes Dev 2000; 14(22): 2799–806PubMedCrossRef

142.

Saxena MT, Schroeter EH, Mumm JS, et al. Murine Notch homologs (N1-4) undergo presenilin-dependent proteolysis. J Biol Chem 2001; 276(43): 40268–73PubMed

143.

LaVoie MJ, Selkoe DJ. The Notch ligands, jagged and delta, are sequentially processed by α-secretase and presenilin/γ-secretase and release signaling fragments. J Biol Chem 2003; 278(36): 34427–37CrossRef

144.

Ikeuchi T, Sisodia SS. The Notch ligands, delta1 and jagged2, are substrates for presenilin-dependent “γ-secretase” cleavage. J Biol Chem 2003; 278(10): 7751–4PubMedCrossRef

145.

Marambaud P, Shioi J, Serban G, et al. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 2002; 21(8): 1948–56PubMedCrossRef

146.

Marambaud P, Wen PH, Dutt A, et al. A CBP binding transcriptional repressor produced by the PS 1/ε-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003; 114(5): 635–45PubMedCrossRef

147.

Haas IG, Frank M, Veron N, et al. Presenilin-dependent processing and nuclear function of gamma-protocadherins. J Biol Chem 2005 Mar 11; 280(10): 9313–9PubMedCrossRef

148.

Lammich S, Okochi M, Takeda M, et al. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Aβ-like peptide. J Biol Chem 2002; 277(47): 44754–9PubMedCrossRef

149.

Murakami D, Okamoto I, Nagano O, et al. Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD 44. Oncogene 2003; 22(10): 1511–6PubMedCrossRef

150.

Andersson CX, Fernandez-Rodriguez J, Laos S, et al. Shedding and γ-secretase mediated intramembrane proteolysis of the mucin-type molecule CD 43. Biochem J 2005 Apr 15; 387 (Pt 2): 377–84PubMedCrossRef

151.

May P, Reddy YK, Herz J. Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J Biol Chem 2002; 277(21): 18736–43PubMedCrossRef

152.

Meyer EL, Strutz N, Gahring LC, et al. Glutamate receptor subunit 3 is modified by site-specific limited proteolysis including cleavage by γ-secretase. J Biol Chem 2003; 278(26): 23786–96PubMedCrossRef

153.

McCarthy JV. Involvement of presenilins in cell-survival signalling pathways. Biochem Soc Trans 2005; 33(4): 568–72PubMedCrossRef

154.

Marambaud P, Robakis NK. Genetic and molecular aspects of Alzheimer’s disease shed light on new mechanisms of transcriptional regulation. Genes Brain Behav 2005 Apr; 4(3): 134–46PubMedCrossRef

155.

Saura CA, Choi SY, Beglopoulos V, et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 2004 Apr 8; 42(1): 23–36PubMedCrossRef

156.

Saura CA, Chen G, Malkani S, et al. Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 2005 Jul 20; 25(29): 6755–64PubMedCrossRef

157.

Coolen MW, Van Loo KM, Van Bakel NN, et al. Gene dosage effect on γ-secretase component Aph-1b in a rat model for neurodevelopmental disorders. Neuron 2005 Feb 17; 45(4): 497–503PubMedCrossRef

158.

Lee HJ, Jung KM, Huang YZ, et al. Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB 4. J Biol Chem 2001; 277(8): 6318–23PubMedCrossRef

159.

Ni CY, Murphy MP, Golde TE, et al. γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001; 294(5549): 2179–81PubMedCrossRef

160.

Kim DY, MacKenzie Ingano LA, Kovacs DM. Nectin-1α, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/γ-secretase-like cleavage. J Biol Chem 2002; 277(51): 49976–81PubMedCrossRef

161.

Schulz JG, Annaert W, Vandekerckhove J. Syndecan 3 intramembrane proteolysis is presenilin/γ-secretase-dependent and modulates cytosolic signaling. J Biol Chem 2003; 278(49): 48651–7PubMedCrossRef

162.

Maretzky T, Schulte M, Ludwig A, et al. Ll is sequentially processed by two differently activated metalloproteases and presenilin/γ-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol 2005 Oct; 25(20): 9040–53PubMedCrossRef

163.

Kanning KC, Hudson M, Amieux PS, et al. Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. J Neurosci 2003; 23(13): 5425–36PubMed

164.

Gowrishankar K, Zeidler MG, Vincenz C. Release of a membrane-bound death domain by a-secretase processing of the p75NTR homolog NRADD. J Cell Sci 2004; 117 (Pt 18): 4099–111PubMedCrossRef

165.

Taniguchi Y, Kim SH, Sisodia SS. Presenilin-dependent “γ-secretase” processing of deleted in colorectal cancer (DCC). J Biol Chem 2003; 278(33): 30425–8PubMedCrossRef

166.

Kim DY, Ingano LA, Carey BW, et al. Presenilin/γ-secretase-mediated cleavage of the voltage-gated sodium channel β2-subunit regulates cell adhesion and migration. J Biol Chem 2005 Jun 17; 280(24): 23251–61PubMedCrossRef

167.

Cowan JW, Wang X, Guan R, et al. Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage. J Biol Chem 2005 May 13; 280(19): 19331–42PubMedCrossRef

168.

Wang R, Tang P, Wang P, et al. Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer’s disease mutation. Proc Natl Acad Sci U S A 2006 Jan 10; 103(2) 353–8PubMedCrossRef

169.

Fuller SJ, Storey E, Li QX, et al. Intracellular production of βA4 amyloid of Alzheimer’s disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein. Biochemistry 1995; 34(25): 8091–8PubMedCrossRef

170.

Higaki J, Quon D, Zhong Z, et al. Inhibition of β-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 1995; 14(3): 651–9PubMedCrossRef

171.

Sernee MF, Evin G, Culvenor JG, et al. Selecting cells with different Alzheimer’s disease γ-secretase activity using FACS: differential effect on presenilin exon 9 γ- and ε-cleavage. Eur J Biochem 2003; 270(3): 495–506PubMedCrossRef

172.

Cao X, Sudhof TC. A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip 60. Science 2001; 293(5527): 115–20PubMedCrossRef

173.

Komano H, Shiraishi H, Kawamura Y, et al. A new functional screening system for identification of regulators for the generation of amyloid β-protein. J Biol Chem 2002; 277(42): 39627–33PubMedCrossRef

174.

Karlstrom H, Bergman A, Lendahl U, et al. A sensitive and quantitative assay for measuring cleavage of presenilin substrates. J Biol Chem 2002; 277(9): 6763–6PubMedCrossRef

175.

Liao YF, Wang BJ, Cheng HT, et al. Tumor necrosis factor-α, interleukin-1 β, and interferon-γ stimulate γ-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem 2004; 279(47): 49523–32PubMedCrossRef

176.

Steiner H, Pesold B, Haass C. An in vivo assay for the identification of target proteases which cleave membrane-associated substrates. FEBS Lett 1999; 463(3): 245–9PubMedCrossRef

177.

McLendon C, Xin T, Ziani-Cherif C, et al. Cell-free assays for γ-secretase activity. FASEB J 2000; 14(15): 2383–6PubMed

178.

Ikeuchi T, Sisodia SS. Cell-free generation of the Notch1 intracellular domain (NICD) and APP-CTFγ. evidence for distinct intramembranous “γ-secretase” activities. Neuromolecular Med 2002; 1(1): 43–54

179.

Pinnix I, Musunuru U, Tun H, et al. A novel γ-secretase assay based on detection of the putative C-terminal fragment-γ of amyloid β protein precursor. J Biol Chem 2001; 276(1): 481–7PubMedCrossRef

180.

Kimberly WT, Esler WP, Ye W, et al. Notch and the amyloid precursor protein are cleaved by similar γ-secretase (s). Biochemistry 2003; 42(1): 137–44PubMedCrossRef

181.

Wrigley JD, Schurov I, Nunn EJ, et al. Functional overexpression of γ-secretase reveals protease-independent trafficking functions and a critical role of lipids for protease activity. J Biol Chem 2005 Apr 1; 280(13): 12523–35PubMedCrossRef

182.

Ogura T, Mio K, Hayashi I, et al. Three-dimensional structure of the gamma-secretase complex. Biochem Biophys Res Commun 2006 May 5; 343(2): 525–34PubMedCrossRef

183.

Klafki H, Abramowski D, Swoboda R, et al. The carboxyl termini of β-amyloid peptides 1-40 and 1-42 are generated by distinct γ-secretase activities. J Biol Chem 1996; 271(45): 28655–9PubMedCrossRef

184.

Esler WP, Kimberly WT, Ostaszewski BL, et al. Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a y substrate. Proc Natl Acad Sci U S A 2002; 99(5): 2720–5PubMedCrossRef

185.

Kornilova AY, Das C, Wolfe MS. Differential effects of inhibitors on the γ-secretase complex: mechanistic implications. J Biol Chem 2003; 278(19): 16470–3PubMedCrossRef

186.

Piper SC, Amtul Z, Galinanes-Garcia L, et al. Peptide-based, irreversible inhibitors of γ-secretase activity. Biochem Biophys Res Commun 2003; 305(3): 529–33PubMedCrossRef

187.

Bihel F, Das C, Bowman MJ, et al. Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of γ-secretase. J Med Chem 2004; 47(16): 3931–3PubMedCrossRef

188.

Kornilova AY, Bihel F, Das C, et al. The initial substrate-binding site of γ-secretase is located on presenilin near the active site. Proc Natl Acad Sci U S A 2005 Mar 1; 102(9): 3230–5PubMedCrossRef

189.

Bunnell WL, Pham HV, Glabe CG. γ-Secretase cleavage is distinct from endoplasmic reticulum degradation of the trans-membrane domain of the amyloid precursor protein. J Biol Chem 1998; 273(48): 31947–55PubMedCrossRef

190.

Skovronsky DM, Pijak DS, Doms RW, et al. A distinct ER/IC γ-secretase competes with the proteasome for cleavage of APP. Biochemistry 2000; 39(4): 810–7PubMedCrossRef

191.

Lewis HD, Perez Revueita BI, Nadin A, et al. Catalytic site-directed γ-secretase complex inhibitors do not discriminate pharmacologically between Notch S3 and β-APP cleavages. Biochemistry 2003; 42(24): 7580–6PubMedCrossRef

192.

Higaki JN, Chakravarty S, Bryant CM, et al. A combinatorial approach to the identification of dipeptide aldehyde inhibitors of β-amyloid production. J Med Chem 1999; 42(19): 3889–98PubMedCrossRef

193.

Citron M, Diehl TS, Gordon G, et al. Evidence that the 42- and 40-amino acid forms of amyloid β protein are generated from the β-amyloid precursor protein by different protease activities. Proc Natl Acad Sci U S A 1996; 93(23): 13170–5PubMedCrossRef

194.

Figueiredo-Pereira ME, Efthimiopoulos S, Tezapsidis N, et al. Distinct secretases, a cysteine protease and a serine protease, generate the C-termini of amyloid β-proteins Aβ1-40 and Aβ1-42, respectively. J Neurochem 1999; 72: 1417–22PubMedCrossRef

195.

196.

Dovey HF, John V, Anderson JP, et al. Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain. J Neurochem 2001; 76(1): 173–81PubMedCrossRef

197.

Comery TA, Martone RL, Aschmies S, et al. Acute γ-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 2005 Sep 28; 25(39): 8898–902PubMedCrossRef

198.

Micchelli CA, Esler WP, Kimberly WT, et al. γ-Secretase/presenilin inhibitors for Alzheimer’s disease phenocopy Notch mutations in Drosophila. FASEB J 2003; 17(1): 79–81PubMed

199.

Geling A, Steiner H, Willem M, et al. A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 2002; 3(7): 688–94PubMedCrossRef

200.

Petit A, Bihel F, Alves da Costa C, et al. New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage. Nat Cell Biol 2001; 3(5): 507–11PubMedCrossRef

201.

Petit A, Pasini A, Alves da Costa C, et al. JLK isocoumarin inhibitors: selective γ-secretase inhibitors that do not interfere with Notch pathway in vitro or in vivo. J Neurosci Res 2003; 74(3): 370–7PubMedCrossRef

202.

Petit A, Dumanchin-Njock C, Andrau D, et al. Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase. Nat Cell Biol 2002; 4(5): E111–2CrossRef

203.

Esler WP, Das C, Campbell WA, et al. Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase. Nat Cell Biol 2002; 4(5): E110–1PubMedCrossRef

204.

Bihel F, Quelever G, Lelouard H, et al. Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new β-amyloid peptide production inhibitors and their activities on various classes of protease. Bioorg Med Chem 2003; 11(14): 3141–52PubMedCrossRef

205.

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 2004; 279(13): 12876–82PubMedCrossRef

206.

Lanz TA, Hosley JD, Adams WJ, et al. Studies of Aβ pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the γ-secretase inhibitor 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 (LY-411575). J Pharmacol Exp Ther 2004; 309(1): 49–55PubMedCrossRef

207.

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 2005 Feb; 312(2): 635–43PubMedCrossRef

208.

Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 2001; 414(6860): 212–616PubMedCrossRef

209.

Takahashi Y, Hayashi I, Tominari Y, et al. Sulindac sulfide is a non-competitive γ-secretase inhibitor that preferentially reduces Aβ42 generation. J Biol Chem 2003; 278(20): 18664–70PubMedCrossRef

210.

Morihara T, Chu T, Ubeda O, et al. Selective inhibition of Aβ42 production by NSAID R-enantiomers. J Neurochem 2002; 83(4): 1009–12PubMedCrossRef

211.

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 2004; 279(42): 43419–26PubMedCrossRef

212.

Weggen S, Eriksen JL, Sagi SA, et al. Aβ42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain. J Biol Chem 2003; 278(33): 30748–54PubMedCrossRef

213.

Harrison T, Churcher I, Beher D. γ-Secretase as a target for drug intervention in Alzheimer’s disease. Curr Opin Drug Discov Devel 2004; 7(5): 709–19PubMed

214.

Lanz TA, Himes CS, Pallante G, et al. The γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces A β levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 2003; 305(3): 864–71PubMedCrossRef

215.

Lleo A, Berezovska O, Herl L, et al. Nonsteroidal anti-inflammatory drugs lower Aβ42 and change presenilin 1 conformation. Nat Med 2004; 10(10): 1065–6PubMedCrossRef

216.

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. Nature 2005 Jun 16; 435(7044): 959–63PubMedCrossRef

217.

Minter LM, Turley DM, Das P, et al. Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx 21. Nat Immunol 2005 Jul; 6(7): 680–8PubMedCrossRef

218.

A Notch signalling pathway inhibitor for patients with advanced breast cancer (sponsored by Merck) [online]. Available from URL: http://www.clinicaltrials.gov/ct/show/NCT00106145 [Accessed 2006 Apr 11]

219.

A Notch signalling pathway inhibitor for patients with T-cell acute lymphoblastic leukemia/lymphoma (sponsored by Merck) [online]. Available from URL: http://www.clinicaltrials.gov/ct/show/NCT00100152 [Accessed 2006 Apr 11]

220.

Beher D, Wrigley JD, Nadin A, et al. Pharmacological knockdown of the presenilin 1 heterodimer by a novel γ-secretase inhibitor: implications for presenilin biology. J Biol Chem 2001; 276(48): 45394–402PubMedCrossRef

221.

Campbell WA, Reed ML, Strahle J, et al. Presenilin endoproteolysis mediated by an aspartyl protease activity pharmacologically distinct from γ-secretase. J Neurochem 2003; 85(6): 1563–74PubMedCrossRef

222.

Tarassishin L, Yin YI, Bassit B, et al. Processing of Notch and amyloid precursor protein by γ-secretase is spatially distinct. Proc Natl Acad Sci U S A 2004 Dec 7; 101(49): 17050–5PubMedCrossRef

223.

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 2005 May 6; 280(18): 17792–7PubMedCrossRef

224.

Phiel CJ, Wilson CA, Lee VM, et al. GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides. Nature 2003; 423(6938): 435–9PubMedCrossRef

225.

Sai X, Kawamura Y, Kokame K, et al. Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid β-protein. J Biol Chem 2002; 277(15): 12915–20PubMedCrossRef

226.

Netzer WJ, Dou F, Cai D, et al. Gleevec inhibits β-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A 2003; 100(21): 12444–9PubMedCrossRef

227.

Fraering PC, Ye W, Lavoie MJ, et al. γ-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide binding site. J Biol Chem 2005 Dec 23; 280(51): 41987–96PubMedCrossRef

228.

Siemers E, Skinner M, Dean RA, et al. Safety, tolerability and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005 May–Jun; 28(3): 126–32PubMedCrossRef

229.

Siemers ER, Quinn JF, Kaye J. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006 Feb 28; 66(4): 602–4PubMedCrossRef

Title: Inhibition of γ-Secretase as a Therapeutic Intervention for Alzheimer’s Disease
Prospects, Limitations and Strategies
Authors: Dr Geneviève Evin
Marijke Fleur Sernee
Colin L. Masters
Publication date: 01-05-2006
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 5/2006
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.2165/00023210-200620050-00002

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Inhibition of γ-Secretase as a Therapeutic Intervention for Alzheimer’s Disease

Prospects, Limitations and Strategies

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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