Presenilins and γ-secretase: Structure, function, and role in Alzheimer disease

Cold Spring Harbor Perspectives in Medicine

Volumn 2, Issue 1, 2012, Pages

  De Strooper, Bart ^a,b   Iwatsubo, Takeshi ^c   Wolfe, Michael S ^d  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

^c UNIVERSITY OF TOKYO   (Japan)

^d HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN [1-40]; AMYLOID BETA PROTEIN [1-42]; AMYLOID PRECURSOR PROTEIN; ANTERIOR PHARYNX DEFECTIVE 1 PROTEIN; ASPARTIC PROTEINASE; BEGACESTAT; BETA CATENIN; BETA1 INTEGRIN; BMS 163; BMS 708; EPIDERMAL GROWTH FACTOR RECEPTOR 4; GAMMA SECRETASE; IMATINIB; MEMBRANE PROTEIN; NERVE CELL ADHESION MOLECULE; NICASTRIN; NOTCH RECEPTOR; PRESENILIN; PRESENILIN 1; PRESENILIN 2; RYANODINE RECEPTOR; SEMAGACESTAT; TARENFLURBIL; UNCLASSIFIED DRUG; UVOMORULIN; AMYLOID BETA PROTEIN; ENZYME INHIBITOR; SECRETASE;

ALZHEIMER DISEASE; AMINO ACID SEQUENCE; ARTICLE; CALCIUM HOMEOSTASIS; CELL DIFFERENTIATION; DRUG TARGETING; GENE INACTIVATION; HUMAN; MISSENSE MUTATION; NONHUMAN; PATHOGENESIS; PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; PROTEIN SUBUNIT; SIGNAL TRANSDUCTION; DRUG ANTAGONISM; DRUG DEVELOPMENT; ENZYMOLOGY; GENETICS; METABOLISM; PHYSIOLOGY; REVIEW; STRUCTURE ACTIVITY RELATION;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID PRECURSOR PROTEIN SECRETASES; DRUG DISCOVERY; ENZYME INHIBITORS; HUMANS; MUTATION, MISSENSE; PRESENILINS; PROTEOLYSIS; RECEPTORS, NOTCH; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84863939887     PISSN: None     EISSN: 21571422     Source Type: Journal    
DOI: 10.1101/cshperspect.a006304     Document Type: Article

References (168)

1. Alzheimer's Disease Collaborative Group. 1995. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 11: 219-222.
2. Baumann K, Paganetti PA, Sturchler-Pierrat C, Wong C, Hartmann H, Cescato R, Frey P, Yankner BA, Sommer B, Staufenbiel M. 1997. Distinct processing of endogenous and overexpressed recombinant presenilin 1. Neurobiol Aging 18: 181-189.
3. Beel AJ, Sanders CR. 2008. Substrate specificity of γ-secretase and other intramembrane proteases. Cell Mol Life Sci 65: 1311-1334.
4. Beher D, Fricker M, Nadin A, Clarke EE, Wrigley JD, Li YM, Culvenor JG, MastersCL, Harrison T, Shearman MS. 2003. In vitro characterization of the presenilin-dependent γ-secretase complex using a novel affinity ligand. Biochemistry 427: 8133-8142.
5. Beher D, Clarke EE, Wrigley JD, Martin AC, Nadin A, Churcher I, Shearman MS. 2004. 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: 43419-43426.
6. Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B. 2006. Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J Neurochem 96: 732-742.
7. Bezprozvanny I, Mattson MP. 2008. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 31: 454-463.
8. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, et al. 1996. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17: 1005-1013.
9. Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS. 1997. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19: 939-945.
10. Capell A, Kaether C, Edbauer D, Shirotani K, Merkl S, Steiner H, Haass C. 2003. Nicastrin interacts with γ-secretase complex components via the N-terminal part of its transmembrane domain. J Biol Chem 278: 52519-52523.
11. Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP. 2000. Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem 275: 18195-18200.
12. Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, et al. 2006. TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature 440: 1208-1212.
13. 2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58: 871-883.
14. Chiang PM, Fortna RR, Price DL, Li T, Wong PC. 2010. Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin. Neurobiol Aging doi: 10. 1016/j. neurobiolaging. 2009. 12. 028.
15. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-WoodK, Lee M, Seubert P, Davis A, et al. 1997. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 3: 67-72.
16. Costa RM, Honjo T, Silva AJ. 2003. Learning and memory deficits in Notch mutant mice. Curr Biol 13: 1348-1354.
17. Costa RM, Drew C, Silva AJ. 2005. Notch to remember. Trends Neurosci 28: 429-435.
18. Crystal AS, Morais VA, Pierson TC, Pijak DS, Carlin D, Lee VM, Doms RW. 2003. Membrane topology of γ-secretase component PEN-2. J Biol Chem 278: 20117-20123.
19. Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR, Carbone DP. 2000. Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. J Natl Cancer Inst 92: 1355-1357.
20. Dejaegere T, Serneels L, Schafer MK, Van Biervliet J, Horre K, Depboylu C, Alvarez-Fischer D, Herreman A, Willem M, Haass C, et al. 2008. Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc Natl Acad Sci 105: 9775-9780.
21. Demehri S, Turkoz A, Kopan R. 2009. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16: 55-66.
22. De Strooper B. 2003. Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex. Neuron 38: 9-12.
23. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. 1998. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391: 387-390.
24. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, et al. 1999. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398: 518-522.
25. Doan A, Thinakaran G, Borchelt DR, Slunt HH, Ratovitsky T, Podlisny M, SelkoeDJ, Seeger M, Gand SE, Price DL, et al. 1996. Protein topology of presenilin 1. Neuron 17: 1023-1030.
26. Doerfler P, Shearman MS, Perlmutter RM. 2001. Presenilin-dependent γ-secretase activity modulates thymocyte development. Proc Natl Acad Sci 98: 9312-9317.
27. Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, et al. 2001. Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain. J Neurochem 76: 173-181.
28. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, et al. 1996. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383: 710-713.
29. Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. 2003. Reconstitution of γ-secretase activity. Nat Cell Biol 5: 486-488.
30. Eggert S, Paliga K, Soba P, Evin G, Masters CL, Weidemann A, Beyreuther K. 2004. 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 279: 18146-18156.
31. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. 1991. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66: 649-661.
32. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, et al. 2003. NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ 42 in vivo. J Clin Invest 112: 440-449.
33. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai J-Y, RahmatiT, Xia W, Selkoe DJ, Wolfe MS. 2000. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nature Cell Biol 2: 428-434.
34. Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ, Wolfe MS. 2002. Activity-dependent isolation of the presenilin/γ-secretase complex reveals nicastrin and a γ substrate. Proc Natl Acad Sci 99: 2720-2725.
35. Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L, ZhengH, Saftig P, De Strooper B, Klumperman J, et al. 2004. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol 166: 1041-1054.
36. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, et al. 2008. Phase 2 safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch Neurol 65: 1031-1038.
37. Flood DG, Reaume AG, Dorfman KS, Lin YG, Lang DM, Trusko SP, Savage MJ, Annaert WG, De Strooper B, Siman R, et al. 2002. FAD mutant PS-1 gene-targeted mice: Increased Aβ42 and Aβ deposition without APP overproduction. Neurobiol Aging 23: 335-348.
38. Fortna RR, Crystal AS, Morais VA, Pijak DS, Lee VM, Doms RW. 2004. Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the γ-secretase complex. J Biol Chem 279: 3685-3693.
39. Fraering PC, LaVoie MJ, Ye W, Ostaszewski BL, Kimberly WT, Selkoe DJ, WolfeMS. 2004a. 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 43: 323-333.
40. Fraering PC, Ye W, Strub JM, Dolios G, LaVoie MJ, Ostaszewski BL, Van Dorsselaer A, Wang R, Selkoe DJ, Wolfe MS. 2004b. Purification and characterization of the human γ-Secretase complex. Biochemistry 43: 9774-9789.
41. Fraering PC, Ye W, Lavoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. 2005. γ-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide binding site. J Biol Chem 280: 41987-41996.
42. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, MaxwellM, Hai B, Ellis MC, et al. 2002. aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev Cell 3: 85-97.
43. Fukumori A, Fluhrer R, Steiner H, Haass C. 2010. Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of γ-secretase-mediated intramembrane proteolysis. J Neurosci 30: 7853-7862.
44. Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, et al. 2007. Safety, tolerability, pharmacokinetics, and Aβ levels after short-term administration of R-flurbiprofen in healthy elderly individuals. Alzheimer Dis Assoc Disord 21: 292-299.
45. Ge X, Hannan F, Xie Z, Feng C, Tully T, Zhou H, Xie Z, Zhong Y. 2004. Notch signaling in Drosophila long-term memory formation. Proc Natl Acad Sci 101: 10172-10176.
46. Georgakopoulos A, Marambaud P, Efthimiopoulos S, Shioi J, Cui W, Li HC, Schutte M, Gordon R, Holstein GR, Martinelli G, et al. 1999. Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Mol Cell 4: 893-902.
47. Gillman KW, Starrett JE, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, Williams R, et al. 2010. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med Chem Lett 1: 120-124.
48. Golde TE, Wolfe MS, Greenbaum DC. 2009. Signal peptide peptidases: A family of intramembrane-cleaving proteases that cleave type 2 transmembrane proteins. Semin Cell Dev Biol 20: 225-230.
49. Goutte C, Hepler W, Mickey KM, Priess JR. 2000. aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development 127: 2481-2492.
50. Goutte C, Tsunozaki M, Hale VA, Priess JR. 2002. APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci 99: 775-779.
51. Grabher C, von Boehmer H, Look AT. 2006. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 6: 347-359.
52. Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM. 2008. SERCA pump activity is physiologically regulated by presenilin and regulates amyloid-β production. J Cell Biol 181: 1107-1116.
53. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz ZH. 2009. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 302: 2557-2564.
54. Gu Y, Chen F, Sanjo N, Kawarai T, Hasegawa H, Duthie M, Li W, Ruan X, LuthraA, Mount HT, et al. 2003. 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 278: 7374-7380.
55. Haass C, Selkoe DJ. 1993. Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75: 1039-1042.
56. Haass C, Selkoe DJ. 1998. Alzheimer's disease. A technical KO of amyloid-β peptide. Nature 391: 339-340.
57. Haass C, Kaether C, Sisodia S, Thinakaran G. 2011. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med doi: 10. 1101/cshperspect. a006270.
58. Hadland BK, Manley NR, Su D, Longmore GD, Moore CL, Wolfe MS, SchroeterEH, Kopan R. 2001. γ-secretase inhibitors repress thymocyte development. Proc Natl Acad Sci 98: 7487-7491.
59. Hayrapetyan V, Rybalchenko V, Rybalchenko N, Koulen P. 2008. The N-terminus of presenilin-2 increases single channel activity of brain ryanodine receptors through direct protein-protein interaction. Cell Calcium 44: 507-518.
60. He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, et al. 2010. γ-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 467: 95-98.
61. Hemming ML, Elias JE, Gygi SP, Selkoe DJ. 2008. Proteomic profiling of γ-secretase substrates and mapping of substrate requirements. PLoS Biol 6: e257.
62. Hu C, Dievart A, Lupien M, Calvo E, Tremblay G, Jolicoeur P. 2006. Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors. Am J Pathol 168: 973-990.
63. Kaether C, Capell A, Edbauer D, Winkler E, Novak B, Steiner H, Haass C. 2004. The presenilin C-terminus is required for ER-retention, nicastrin-binding and γ-secretase activity. Embo J 23: 4738-4748.
64. 2+ content in presenilin double knock-out cells. Cell Calcium 40: 41-51.
65. Khandelwal A, Chandu D, Roe CM, Kopan R, Quatrano RS. 2007. Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionarily conserved. Proc Natl Acad Sci 104: 13337-13342.
66. Kim SH, Sisodia SS. 2005. Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. J Biol Chem 280: 41953-41966.
67. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. 2003. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2. Proc Natl Acad Sci 100: 6382-6387.
68. Kopan R, Ilagan MX. 2004. γ-Secretase: Proteasome of the membrane?. Nat Rev Mol Cell Biol 5: 499-504.
69. Kornilova AY, Bihel F, Das C, Wolfe MS. 2005. The initial substrate binding site of γ-secretase is located on presenilin near the active site. Proc Natl Acad Sci 102: 3230-3235.
70. Kreft AF, Martone R, Porte A. 2009. Recent advances in the identification of γ-secretase inhibitors to clinically test the Aβ oligomer hypothesis of Alzheimer's disease. J Med Chem 52: 6169-6188.
71. Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH, Golde TE, Nicolle MM. 2007. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci 8: 54.
72. Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R, Maharvi GM, Healy B, Chapman R, Welzel AT, Price RW, et al. 2008. Substrate-targeting γ-secretase modulators. Nature 453: 925-929.
73. Kulic L, Walter J, Multhaup G, Teplow DB, Baumeister R, Romig H, Capell A, Steiner H, Haass C. 2000. Separation of presenilin function in amyloid β-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci 97: 5913-5918.
74. Lanz TA, Hosley JD, Adams WJ, Merchant KM. 2004. 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-di hydro-5H-dibenzo[b, d]azepin-7-yl]-L-alaninamide (LY-411575). J Pharmacol Exp Ther 309: 49-55.
75. Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL, Pozdnyakov N, Martin BA, Du P, Oborski CE, Wood DE, et al. 2010. Pharmacodynamics and pharmacokinetics of the γ-secretase inhibitor, PF-3084014. J Pharmacol Exp Ther 334: 269-277.
76. Laudon H, Hansson EM, Melen K, Bergman A, Farmery MR, Winblad B, LendahlU, von Heijne G, Naslund J. 2005. A nine-transmembrane domain topology for presenilin 1. J Biol Chem 280: 35352-35360.
77. LaVoie MJ, Fraering PC, Ostaszewski BL, Ye W, Kimberly WT, Wolfe MS, SelkoeDJ. 2003. Assembly of the γ-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin. J Biol Chem 278: 37213-37222.
78. Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H. 2006. Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci 103: 6889-6894.
79. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, et al. 2010. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141: 1146-1158.
80. Leissring MA, Paul BA, Parker I, Cotman CW, LaFerla FM. 1999. Alzheimer's presenilin-1 mutation potentiates inositol 1, 4, 5-trisphosphate-mediated calcium signaling in Xenopus oocytes. J Neurochem 72: 1061-1068.
81. Levitan D, Greenwald I. 1995. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377: 351-354.
82. Levitan D, Yu G, St George Hyslop P, Goutte C. 2001. APH-2/nicastrin functions in LIN-12/Notch signaling in the Caenorhabditis elegans somatic gonad. Dev Biol 240: 654-661.
83. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, YuCE, Jondro PS, Schmidt SD, Wang K, et al. 1995. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269: 973-977.
84. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, LellisC, Nadin A, Neduvelil JG, et al. 2000. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405: 689-694.
85. Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, Fan X, Crain BJ, Price DL, Golde TE, et al. 2007. Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of γ-secretase. J Biol Chem 282: 32264-32273.
86. Ma G, Li T, Price DL, Wong PC. 2005. APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development. J Neurosci 25: 192-198.
87. Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, et al. 2002. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. Embo J 21: 1948-1956.
88. Marambaud P, Wen PG, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK. 2003. A CBP binding transcriptional repressor produced by the PS1/ε-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114: 635-645.
89. Mayer SC, Kreft AF, Harrison B, Abou-Gharbia M, Antane M, Aschmies S, Atchison K, Chlenov M, Cole DC, Comery T, et al. 2008. Discovery of begacestat, a Notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer's disease. J Med Chem 51: 7348-7351.
90. McCarthy JV, Twomey C, Wujek P. 2009. Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity. Cell Mol Life Sci 66: 1534-1555.
91. Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, Kaether C, Zheng H, Ghetti B, Haass C, et al. 2002. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ 42 production. Proc Natl Acad Sci 99: 8025-8030.
92. Mucke L. 2011. Neurotoxicity of amyloid β-protein: Synaptic and network dysfunction. Cold Spring Harb Perspect Med doi: 10. 1101/cshperspect. a006338.
93. Müller UC, Zheng H. 2011. Physiological functions of APP family proteins. Cold Spring Harb Perspect Med doi: 10. 1101/cshperspect. a006288.
94. Naruse S, Thinakaran G, Luo JJ, Kusiak JW, Tomita T, Iwatsubo T, Qian X, GintyDD, Price DL, Borchelt DR, et al. 1998. Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21: 1213-1221.
95. 2+ leak function of presenilin 1. J Clin Invest 117: 1230-1239.
96. Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, XuH, Greengard P. 2003. Gleevec inhibits β-amyloid production but not Notch cleavage. Proc Natl Acad Sci 100: 12444-12449.
97. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, Hui CC, Clevers H, Dotto GP, Radtke F. 2003. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33: 416-441.
98. Nyabi O, Bentahir M, Horre K, Herreman A, Gottardi-Littell N, Van BroeckhovenC, Merchiers P, Spittaels K, Annaert W, De Strooper B. 2003. Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin. J Biol Chem 278: 43430-43436.
99. Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, Kopan R, Kodama T, Hamakubo T, Iwatsubo T, Tomita T, et al. 2006. Three-dimensional structure of the γ-secretase complex. Biochem Biophys Res Commun 343: 525-534.
100. Osenkowski P, Li H, Ye W, Li D, Aeschbach L, Fraering PC, Wolfe MS, Selkoe DJ, Li H. 2009. Cryoelectron microscopy structure of purified γ-secretase at 12 A resolution. J Mol Biol 385: 642-652.
101. Pardossi-Piquard R, Yang SP, Kanemoto S, Gu Y, Chen F, Bohm C, Sevalle J, LiT, Wong PC, Checler F, et al. 2009. APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes. J Biol Chem 284: 16298-16307.
102. Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, EberhartCG, Shih Ie M, Wang TL. 2006. Notch3 gene amplification in ovarian cancer. Cancer Res 66: 6312-6318.
103. Pear WS, Aster JC. 2004. T cell acute lymphoblastic leukemia/lymphoma: A human cancer commonly associated with aberrant NOTCH1 signaling. Curr Opin Hematol 11: 426-433.
104. Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. 2002. Identification of a novel family of presenilin homologues. Hum Mol Genet 11: 1037-1044.
105. Presente A, Boyles RS, Serway CN, de Belle JS, Andres AJ. 2004. Notch is required for long-term memory in Drosophila. Proc Natl Acad Sci 101: 1764-1768.
106. Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J, Millar SE, Pear WS, Parmacek MS. 2006. Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 66: 7438-7444.
107. Qyang Y, Chambers SM, Wang P, Xia X, Chen X, Goodell MA, Zheng H. 2004. Myeloproliferative disease in mice with reduced presenilin gene dosage: Effect of γ-secretase blockage. Biochemistry 43: 5352-5359.
108. Reinhard C, Hebert SS, De Strooper B. 2005. The amyloid-β precursor protein: Integrating structure with biological function. EMBO J 24: 3996-4006.
109. Repetto E, Yoon IS, Zheng H, Kang DE. 2007. Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway. J Biol Chem 282: 31504-31516.
110. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, LinC, Holman K, Tsuda T, et al. 1995. 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 376: 775-778.
111. Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G. 2006. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 127: 185-197.
112. Sato C, Morohashi Y, Tomita T, Iwatsubo T. 2006. Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. J Neurosci 26: 12081-12088.
113. Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y, De Strooper B, Steiner H, Haass C, Wolfe MS. 2007. Active γ-secretase complexes contain only one of each component. J Biol Chem 282: 33985-33993.
114. Sato C, Takagi S, Tomita T, Iwatsubo T. 2008. 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: 6264-6271.
115. Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana RaoBS, Chattarji SRS, Kelleher RJ III., Kandel ER, Duff K, et al. 2004. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42: 23-36.
116. Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. 2008. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci 105: 5585-5590.
117. Scheinfeld MH, Ghersi E, Laky K, Fowlkes BJ, D'Adamio L. 2002. Processing of β-amyloid precursor-like protein-1 and-2 by γ-secretase regulates transcription. J Biol Chem 277: 44195-44201.
118. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, et al. 1996. 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: 864-870.
119. Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, Lewis HD, Saxena MT, De Strooper D, Coonrod A, et al. 2003. A presenilin dimer at the core of the γ-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci 100: 13075-13080.
120. Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, BerridgeBR, Gao H, Higgins MA, May PC, Ryan TP. 2003. Adipsin: A biomarker of gastrointestinal toxicity mediated by a functional γsecretase inhibitor. J Biol Chem 278: 46107-46116.
121. Serneels L, Dejaegere T, Craessaerts K, Horre K, Jorissen E, Tousseyn T, HebertS, Coolen M, Martens G, Zwijsen A, et al. 2005. Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc Natl Acad Sci 102: 1719-1724.
122. Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horre K, Van Houtvin T, Esselmann H, Paul S, Schafer MK, Berezovska O, et al. 2009. γ-Secretase heterogeneity in the Aph1 subunit: Relevance for Alzheimer's disease. Science 324: 639-642.
123. Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, Nadin A, Smith AL, Stevenson G, Castro JL. 2000. L-685, 458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid β-protein precursor γ-secretase activity. Biochemistry 39: 8698-8704.
124. Shen J, Kelleher RJ III. 2007. The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci 104: 403-409.
125. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, LinC, Li G, Holman K, et al. 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375: 754-760.
126. Shih Ie M, Wang TL. 2007. Notch signaling, γ-secretase inhibitors, and cancer therapy. Cancer Res 67: 1879-1882.
127. Shirotani K, Edbauer D, Capell A, Schmitz J, Steiner H, Haass C. 2003. γ-Secretase activity is associated with a conformational change of nicastrin. J Biol Chem 278: 16474-16477.
128. Siman R, Reaume AG, Savage MJ, Trusko S, Lin YG, Scott RW, Flood DG. 2000. Presenilin-1 P264L knock-in mutation: Differential effects on Aβ production, amyloid deposition, and neuronal vulnerability. J Neurosci 20: 8717-8726.
129. Sobhanifar S, Schneider B, Lohr F, Gottstein F, Ikeya T, Mlynarczyk K, PulawskiW, Ghoshdastider U, Kolinski M, Filipek S, et al. 2010. Structural investigation of the C-terminal catalytic fragment of presenilin 1. Proc Natl Acad Sci 107: 9644-9649.
130. Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA. 1999. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci 96: 6959-6963.
131. Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W. 2006. Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway. J Biol Chem 281: 26569-26577.
132. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, et al. 2002. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71: 877-892.
133. Steiner H, Kostka M, Romig H, Basset G, Pesold B, Hardy JA, Capell A, Meyn L, Grim MG, Baumeister R, et al. 2000. Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nature Cell Biol 2: 848-851.
134. Steiner H, Winkler E, Haass C. 2008. Chemical crosslinking provides a model of the γ-secretase complex subunit architecture and evidence for close proximity of the C-terminal fragment of presenilin with APH-1. J Biol Chem 283: 34677-34686.
135. Struhl G, Greenwald I. 1999. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398: 522-525.
136. Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo T. 2010. Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase. J Neurosci 30: 15943-15950.
137. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. 2003. The role of presenilin cofactors in the γ-secretase complex. Nature 422: 438-441.
138. Tammam J, Ware C, Efferson C, O'Neil J, Rao S, Qu X, Gorenstein J, Angagaw M, Kim H, Kenific C, et al. 2009. Down-regulation of the Notch pathway mediated by a γ-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. Br J Pharmacol 158: 1183-1195.
139. Teranishi Y, Hur JY, Welander H, Franberg J, Aoki M, Winblad B, Frykman S, Tjernberg LO. 2009. Affinity pulldown of γ-secretase and associated proteins from human and rat brain. J Cell Mol Med 14: 2675-2686.
140. Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, et al. 1996. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17: 181-190.
141. Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL, Borchelt DR, Sisodia SS. 1997. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 272: 28415-28422.
142. Tolia A, Chavez-Gutierrez L, De Strooper B. 2006. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the γ-secretase complex. J Biol Chem 281: 27633-27642.
143. Tolia A, Horre K, De Strooper B. 2008. Transmembrane domain 9 of presenilin determines the dynamic conformation of the catalytic site of γ-secretase. J Biol Chem 283: 19793-19803.
144. Tournoy J, Bossuyt X, Snellinx A, Regent M, Garmyn M, Serneels L, Saftig P, Craessaerts K, De Strooper B, Hartmann D. 2004. Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. Hum Mol Genet 13: 1321-1331.
145. 2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126: 981-993.
146. van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, et al. 2005. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959-963.
147. Wakabayashi T, De Strooper B. 2008. Presenilins: Members of the γ-secretase quartets, but part-time soloists too. Physiology (Bethesda) 23: 194-204.
148. Wakabayashi T, Craessaerts K, Bammens L, Bentahir M, Borgions F, HerdewijnP, Staes A, Timmerman E, Vandekerckhove J, Rubinstein E, et al. 2009. Analysis of the γ-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat Cell Biol 11: 1340-1346.
149. Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, Mattson MP, FurukawaK. 2004. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci 101: 9458-9462.
150. Wang B, Yang W, Wen W, Sun J, Su B, Liu B, Ma D, Lv D, Wen Y, Qu T, et al. 2010. γ-Secretase gene mutations in familial acne inversa. Science 330: 1065.
151. Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T. 2005. Pen-2 is incorporated into the γ-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 280: 41967-41975.
152. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, SmithTE, Murphy MP, Bulter T, et al. 2001. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414: 212-216.
153. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B. 2002. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296: 2215-2218.
154. Weng AP, Ferrando AA, Lee W, Morris JPT, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. 2004. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306: 269-271.
155. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C. 2006. Control of peripheral nerve myelination by the β-secretase BACE1. Science 314: 664-666.
156. Wilson CA, Murphy DD, Giasson BI, Zhang B, Trojanowski JQ, Lee VM. 2004. Degradative organelles containing mislocalized α-and β-synuclein proliferate in presenilin-1 null neurons. J Cell Biol 165: 335-346.
157. Wines-Samuelson M, Schulte EC, Smith MJ, Aoki C, Liu X, Kelleher RJ III., ShenJ. 2010. Characterization of age-dependent and progressive cortical neuronal degeneration in presenilin conditional mutant mice. PLoS One 5: e10195.
158. Winkler E, Hobson S, Fukumori A, Dumpelfeld B, Luebbers T, Baumann K, Haass C, Hopf C, Steiner H. 2009. Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human γ-secretase. Biochemistry 48: 1183-1197.
159. Wolfe MS, Kopan R. 2004. Intramembrane proteolysis: Theme and variations. Science 305: 1119-1123.
160. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Donkor IO, Selkoe DJ. 1999a. Peptidomimetic probes and molecular modeling suggest Alzheimer's γ-secretases are intramembrane-cleaving aspartyl proteases. Biochemistry 38: 4720-4727.
161. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. 1999b. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398: 513-517.
162. Wolfe MS, De Los Angeles J, Miller DD, Xia W, Selkoe DJ. 1999c. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease. Biochemistry 38: 11223-11230.
163. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, et al. 2004. 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: 12876-12882.
164. Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, Koo EH, Wu X, Zheng H. 2001. Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci 98: 10863-10868.
165. Yanagida K, Okochi M, Tagami S, Nakayama T, Kodama TS, Nishitomi K, JiangJ, Mori K, Tatsumi S, Arai T, et al. 2009. The 28-amino acid form of an APLP1-derived Aβ-like peptide is a surrogate marker for Aβ42 production in the central nervous system. EMBO Mol Med 1: 223-235.
166. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, et al. 2000. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407: 48-54.
167. Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Sudhof TC, Shen J. 2009. Presenilins are essential for regulating neurotransmitter release. Nature 460: 632-636.
168. Zou K, Hosono T, Nakamura T, Shiraishi H, Maeda T, Komano H, YanagisawaK, Michikawa M. 2008. Novel role of presenilins in maturation and transport of integrin β1. Biochemistry 47: 3370-3378.