γ-Secretase And Alzheimer’S Disease

  • Michael S. Wolfe
Part of the Proteases in Biology and Disease book series (PBAD, volume 6)


Deposition of the amyloid β-protein is a defining pathological characteristic of Alzheimer’s disease, and this small protein is proteolytically produced from the amyloid β-protein precursor. ,-Secretase is responsible for the second cut, which forms the C-terminus of amyloid-β and determines how much of the transmembrane domain is included in this aggregation-prone protein. This intramembrane aspartyl protease is a complex of four different integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. During assembly and maturation of the protease complex, presenilin is endoproteolyzed into two subunits, each of which contributes one aspartate to the active site. A model of successive proteolysis may explain how Alzheimer-causing mutations in presenilin can both decrease enzyme activity and increase the proportion of longer, more aggregation-prone forms of amyloid-β. Substrate apparently interacts with an initial docking site before passing in whole or in part between the two presenilin subunits to the internal water-containing active site. The ectodomain of nicastrin also interacts with the N-terminus of the substrate as an essential step in substrate recognition and processing. Inhibitors and allosteric modulators of γ-secretase activity are under investigation as potential Alzheimer therapeutics. Elucidation of detailed structural features of γ-secretase is the next logical step toward understanding how this enzyme carries out intramembrane proteolysis and will set the stage for structure-based drug design


amyloid β-protein amyloid β-protein precursor presenilin inhibitors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Annaert, W.G., Esselens, C. Baert, V. Boeve, C. Snellings, G. Cupers, P. Craessaerts, K. and De Strooper, B. 2001. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 32: 579–589.PubMedCrossRefGoogle Scholar
  2. Arawaka, S. Hasegawa, H. Tandon, A. Janus, C. Chen, F. Yu, G. Kikuchi, K. Koyama, S. Kato,T., Fraser, P.E. , et al., 2002. The levels of mature glycosylated nicastrin are regulated and correlate with gamma-secretase processing of amyloid beta-precursor protein. J Neurochem 83: 1065–1071.PubMedCrossRefGoogle Scholar
  3. Baki, L. Shioi, J. Wen, P. Shao, Z. Schwarzman, A. Gama-Sosa, M. Neve, R. and Robakis, N.K., 2004. PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 23: 2586–2596.PubMedCrossRefGoogle Scholar
  4. Beher, D. Clarke, E.E., Wrigley, J.D., Martin, A.C., Nadin, A. Churcher, I. and Shearman, M.S., 2004. Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism. J Biol Chem 279: 43419–43426.PubMedCrossRefGoogle Scholar
  5. Bentahir, M. Nyabi, O. Verhamme, J. Tolia, A. Horre, K. Wiltfang, J. Esselmann, H. and De Strooper, B. 2006. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 96: 732–742.PubMedCrossRefGoogle Scholar
  6. Bihel, F. Das, C. Bowman, M.J., and Wolfe, M.S., 2004. Discovery of a subnanomolar helical D-tridecapeptide inhibitor of β-secretase. J Med Chem 47: 3931–3933.PubMedCrossRefGoogle Scholar
  7. Brunkan, A.L., Martinez, M. Wang, J. Walker, E.S., Beher, D. Shearman, M.S., and Goate, A.M., 2005. Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity. J Neurochem 94: 1315–1328.PubMedCrossRefGoogle Scholar
  8. Cai, X.D., Golde, T.E., and Younkin, S.G., 1993. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259: 514–516.PubMedCrossRefGoogle Scholar
  9. Capell, A. Grunberg, J. Pesold, B. Diehlmann, A. Citron, M. Nixon, R. Beyreuther, K. Selkoe, D.J., and Haass, C. 1998. The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J Biol Chem 273: 3205–3211.PubMedCrossRefGoogle Scholar
  10. Capell, A. Kaether, C. Edbauer, D. Shirotani, K. Merkl, S. Steiner, H. and Haass, C. 2003. Nicastrin interacts with gamma-secretase complex components via the N-terminal part of its transmembrane domain. J Biol Chem 278: 52519–52523.PubMedCrossRefGoogle Scholar
  11. Cervantes, S. Saura, C.A., Pomares, E. Gonzalez-Duarte, R. and Marfany, G. 2004. Functional implications of the presenilin dimerization. Reconstitution of gamma -secretase activity by assembly of a catalytic site at the dimer interface of two catalytically inactive presenilins. J Biol Chem 25: 25.Google Scholar
  12. Citron, M. Oltersdorf, T. Haass, C. McConlogue, L. Hung, A.Y., Seubert, P. Vigo-Pelfrey, C. Lieberburg, I. and Selkoe, D.J., 1992. Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360: 672–674.PubMedCrossRefGoogle Scholar
  13. Citron, M. Westaway, D. Xia, W. Carlson, G. Diehl, T. Levesque, G. Johnson-Wood, K. Lee, M. Seubert, P. Davis, A. , et al., 1997. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3: 67–72.PubMedCrossRefGoogle Scholar
  14. Crystal, A.S., Morais, V.A., Pierson, T.C., Pijak, D.S., Carlin, D. Lee, V.M., and Doms, R.W., 2003. Membrane topology of gamma -secretase component PEN-2. J Biol Chem 14: 14.Google Scholar
  15. Das, C. Berezovska, O. Diehl, T.S., Genet, C. Buldyrev, I. Tsai, J.Y., Hyman, B.T., and Wolfe, M.S., 2003. Designed helical peptides inhibit an intramembrane protease. J Am Chem Soc 125: 11794–11795.PubMedCrossRefGoogle Scholar
  16. De Strooper, B. Annaert, W. Cupers, P. Saftig, P. Craessaerts, K. Mumm, J.S., Schroeter, E.H., Schrijvers, V. Wolfe, M.S., Ray, W.J. , et al., 1999. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398: 518–522.PubMedCrossRefGoogle Scholar
  17. De Strooper, B. Saftig, P. Craessaerts, K. Vanderstichele, H. Guhde, G. Annaert, W. Von Figura, K., and Van Leuven, F. 1998. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391: 387–390.PubMedCrossRefGoogle Scholar
  18. Doan, A. Thinakaran, G. Borchelt, D.R., Slunt, H.H., Ratovitsky, T. Podlisny, M. Selkoe, D.J., Seeger, M., Gandy, S.E., Price, D.L. , et al., 1996. Protein topology of presenilin 1. Neuron 17: 1023–1030.PubMedCrossRefGoogle Scholar
  19. Duff, K. Eckman, C. Zehr, C. Yu, X. Prada, C.M., Perez-tur, J. Hutton, M. Buee, L. Harigaya, Y. Yager, D. , et al., 1996. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383: 710–713.PubMedCrossRefGoogle Scholar
  20. Edbauer, D. Winkler, E. Haass, C. and Steiner, H. 2002. Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Proc Natl Acad Sci U S A 99: 8666–8671.PubMedGoogle Scholar
  21. Edbauer, D. Winkler, E. Regula, J.T., Pesold, B. Steiner, H. and Haass, C. 2003. Reconstitution of gamma-secretase activity. Nat Cell Biol 5: 486–488.PubMedCrossRefGoogle Scholar
  22. Esler, W.P., Kimberly, W.T., Ostaszewski, B.L., Diehl, T.S., Moore, C.L., Tsai, J.-Y., Rahmati, T. Xia, W. Selkoe, D.J., and Wolfe, M.S., 2000. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat Cell Biol 2: 428–434.PubMedCrossRefGoogle Scholar
  23. Esler, W.P., Kimberly, W.T., Ostaszewski, B.L., Ye, W. Diehl, T.S., Selkoe, D.J., and Wolfe, M.S., 2002. Activity-dependent isolation of the presenilin/γ-secretase complex reveals nicastrin and a γ substrate. Proc Natl Acad Sci USA 99: 2720–2725.PubMedCrossRefGoogle Scholar
  24. Fraering, P.C., LaVoie, M.J., Ye, W. Ostaszewski, B.L., Kimberly, W.T., Selkoe, D.J., and Wolfe, M.S., 2004a. Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. Biochemistry 43: 323–333.CrossRefGoogle Scholar
  25. Fraering, P.C., Ye, W. Lavoie, M.J., Ostaszewski, B.L., Selkoe, D.J., and Wolfe, M.S., 2005. gamma -Secretase substrate selectivity can be modulated directly via interaction with a nucleotide binding site. J Biol Chem 280: 41987–41996.PubMedCrossRefGoogle Scholar
  26. Fraering, P.C., Ye, W. Strub, J.M., Dolios, G. LaVoie, M.J., Ostaszewski, B.L., Van Dorsselaer, A. Wang, R. Selkoe, D.J., and Wolfe, M.S., 2004b. Purification and Characterization of the Human gamma-Secretase Complex. Biochemistry 43: 9774–9789.CrossRefGoogle Scholar
  27. Francis, R. McGrath, G. Zhang, J. Ruddy, D.A., Sym, M. Apfeld, J. Nicoll, M. Maxwell, M. Hai, B. Ellis, M.C. , et al., 2002. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 3: 85–97.PubMedCrossRefGoogle Scholar
  28. Fukumori, A. Okochi, M. Tagami, S. Jiang, J. Itoh, N. Nakayama, T. Yanagida, K. Ishizuka-Katsura, Y. Morihara, T. Kamino, K. , et al., 2006. Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct. Biochemistry 45: 4907–4914.PubMedCrossRefGoogle Scholar
  29. Funamoto, S. Morishima-Kawashima, M. Tanimura, Y. Hirotani, N. Saido, T.C., and Ihara, Y. 2004. Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42. Biochemistry 43: 13532–13540.PubMedCrossRefGoogle Scholar
  30. Glenner, G.G., and Wong, C.W., 1984. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Comm 120: 885–890.PubMedCrossRefGoogle Scholar
  31. Goutte, C. Hepler, W. Mickey, K.M., and Priess, J.R., 2000. aph-2 encodes a novel extracellular protein required for GLP-1-mediated signaling. Development 127: 2481–2492.PubMedGoogle Scholar
  32. Gu, Y. Chen, F. Sanjo, N. Kawarai, T. Hasegawa, H. Duthie, M. Li, W. Ruan, X. Luthra, A. Mount,H.T. , et al., 2002. 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.PubMedCrossRefGoogle Scholar
  33. Hardy, J. 1997. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20: 154–159.PubMedCrossRefGoogle Scholar
  34. Hebert, S.S., Godin, C. Tomiyama, T. Mori, H. and Levesque, G. 2003. Dimerization of presenilin-1 in vivo: suggestion of novel regulatory mechanisms leading to higher order complexes. Biochem Biophys Res Commun 301: 119–126.PubMedCrossRefGoogle Scholar
  35. Huppert, S.S., Ilagan, M.X., De Strooper, B. and Kopan, R. 2005. Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation. Dev Cell 8: 677–688.PubMedCrossRefGoogle Scholar
  36. Iwatsubo, T. Odaka, A. Suzuki, N. Mizusawa, H. Nukina, N. and Ihara, Y. 1994. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13: 45–53.PubMedCrossRefGoogle Scholar
  37. Kaether, C. Capell, A. Edbauer, D. Winkler, E. Novak, B. Steiner, H. and Haass, C. 2004. The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J 23: 4738–4748.PubMedCrossRefGoogle Scholar
  38. Kakuda, N. Funamoto, S. Yagishita, S. Takami, M. Osawa, S. Dohmae, N. and Ihara, Y. 2006. Equimolar production of amyloid beta-protein and amyloid precursor protein intracellular domain from beta-carboxyl-terminal fragment by gamma-secretase. J Biol Chem 281: 14776–14786.PubMedCrossRefGoogle Scholar
  39. Kang, D. Soriano, S. Xia, X. Eberhart, C. De Strooper, B. Zheng, H. and Koo, E. 2002. Presenilin Couples the Paired Phosphorylation of beta-Catenin Independent of Axin. Implications for beta-Catenin Activation in Tumorigenesis. Cell 110: 751.Google Scholar
  40. Kim, J. and Schekman, R. 2004. The ins and outs of presenilin 1 membrane topology. Proc Natl Acad Sci U S A 101: 905–906.PubMedCrossRefGoogle Scholar
  41. Kim, S.H., and Sisodia, S.S., 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.PubMedCrossRefGoogle Scholar
  42. Kimberly, W.T., LaVoie, M.J., Ostaszewski, B.L., Ye, W. Wolfe, M.S., and Selkoe, D.J., 2002. Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation. J Biol Chem 277: 35113–35117.PubMedCrossRefGoogle Scholar
  43. Kimberly, W.T., LaVoie, M.J., Ostaszewski, B.L., Ye, W. Wolfe, M.S., and Selkoe, D.J., 2003. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2. Proc Natl Acad Sci U S A 100: 6382–6387.PubMedCrossRefGoogle Scholar
  44. Kopan, R. and Ilagan, M.X., 2004. Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 5: 499–504.PubMedCrossRefGoogle Scholar
  45. Kornilova, A.Y., Bihel, F. Das, C. and Wolfe, M.S., 2005. The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. Proc Natl Acad Sci U S A 102: 3230–3235.PubMedCrossRefGoogle Scholar
  46. Kornilova, A.Y., Das, C. and Wolfe, M.S., 2003. Differential Effects of Inhibitors on the gamma-Secretase Complex. Mechanistic Implications. J Biol Chem 278: 16470–16473.PubMedCrossRefGoogle Scholar
  47. Kornilova, A.Y., Kim, J. Laudon, H. and Wolfe, M.S., 2006. Deducing the transmembrane domain organization of presenilin-1 in γ-secretase by cysteine disulfide cross-linking. Biochemistry : in press.Google Scholar
  48. L’Hernault, S.W., and Arduengo, P.M., 1992. Mutation of a putative sperm membrane protein in Caenorhabditis elegans prevents sperm differentiation but not its associated meiotic divisions. J Cell Biol 119: 55–68.PubMedCrossRefGoogle Scholar
  49. Lai, M.T., Chen, E. Crouthamel, M.C., DiMuzio-Mower, J. Xu, M. Huang, Q. Price, E. Register, R.B., Shi, X.P., Donoviel, D.B. , et al., 2003. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem 278: 22475–22481.PubMedCrossRefGoogle Scholar
  50. Laudon, H. Hansson, E.M., Melen, K. Bergman, A. Farmery, M.R., Winblad, B. Lendahl, U. von Heijne, G. and Naslund, J. 2005. A nine-transmembrane domain topology for presenilin 1. J Biol Chem 280: 35352–35360.PubMedCrossRefGoogle Scholar
  51. Laudon, H. Karlstrom, H. Mathews, P.M., Farmery, M.R., Gandy, S.E., Lundkvist, J. Lendahl, U. and Naslund, J. 2004. Functional domains in presenilin 1: the Tyr-288 residue controls gamma-secretase activity and endoproteolysis. J Biol Chem 279: 23925–23932.PubMedCrossRefGoogle Scholar
  52. LaVoie, M.J., Fraering, P.C., Ostaszewski, B.L., Ye, W. Kimberly, W.T., Wolfe, M.S., and Selkoe, D.J., 2003. Assembly of the gamma-Secretase Complex Involves Early Formation of an Intermediate Subcomplex of Aph-1 and Nicastrin. J Biol Chem 278: 37213–37222.PubMedCrossRefGoogle Scholar
  53. Lazarov, V.K., Fraering, P.C., Ye, W. Wolfe, M.S., Selkoe, D.J., and Li, H. Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci U S A 103: 6889–6894.Google Scholar
  54. Leem, J.Y., Vijayan, S. Han, P. Cai, D. Machura, M. Lopes, K.O., Veselits, M.L., Xu, H. and Thinakaran, G. 2002. Presenilin 1 is required for maturation and cell surface accumulation of nicastrin. J Biol Chem 277: 19236–19240.PubMedCrossRefGoogle Scholar
  55. Lemere, C.A., Lopera, F. Kosik, K.S., Lendon, C.L., Ossa, J. Saido, T.C., Yamaguchi, H. Ruiz, A., Martinez, A. Madrigal, L. , et al., 1996. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med 2: 1146–1150.PubMedCrossRefGoogle Scholar
  56. Levitan, D. and Greenwald, I. 1995. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377: 351–354.PubMedCrossRefGoogle Scholar
  57. Levy-Lahad, E. Wasco, W. Poorkaj, P. Romano, D.M., Oshima, J. Pettingell, W.H., Yu, C.E., Jondro, P.D., Schmidt, S.D., Wang, K. , et al., 1995. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269: 973–977.PubMedCrossRefGoogle Scholar
  58. Lewis, P.A., Perez-Tur, J. Golde, T.E., and Hardy, J. 2000. The presenilin 1 C92S mutation increases abeta 42 production. Biochem Biophys Res Commun 277: 261–263.PubMedCrossRefGoogle Scholar
  59. Li, T. Ma, G. Cai, H. Price, D.L., and Wong, P.C., 2003. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals. J Neurosci 23: 3272–3277.PubMedGoogle Scholar
  60. Li, X. and Greenwald, I. 1996. Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17: 1015–1021.PubMedCrossRefGoogle Scholar
  61. Li, X. and Greenwald, I. 1998. Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc Natl Acad Sci U S A 95: 7109–7114.PubMedCrossRefGoogle Scholar
  62. Li, Y.M., Xu, M. Lai, M.T., Huang, Q. Castro, J.L., DiMuzio-Mower, J. Harrison, T. Lellis, C. Nadin, A., Neduvelil, J.G. , et al., 2000. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405: 689–694.PubMedCrossRefGoogle Scholar
  63. Luo, W.J., Wang, H. Li, H. Kim, B.S., Shah, S. Lee, H.J., Thinakaran, G. Kim, T.W., Yu, G. and Xu, H. 2003. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem 278: 7850–7854.PubMedCrossRefGoogle Scholar
  64. Mackinnon, R. 2005. Structural biology. Membrane protein insertion and stability. Science 307: 1425–1426.PubMedCrossRefGoogle Scholar
  65. 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 Abeta 42 production. Proc Natl Acad Sci U S A 99: 8025–8030.PubMedCrossRefGoogle Scholar
  66. Morais, V.A., Crystal, A.S., Pijak, D.S., Carlin, D. Costa, J. Lee, V.M., and Doms, R.W., 2003. The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex. J Biol Chem 278: 43284–43291.PubMedCrossRefGoogle Scholar
  67. Netzer, W.J., Dou, F. Cai, D. Veach, D. Jean, S. Li, Y. Bornmann, W.G., Clarkson, B. Xu, H. and Greengard, P. 2003. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A 100: 12444–12449.PubMedCrossRefGoogle Scholar
  68. Nyborg, A.C., Kornilova, A.Y., Jansen, K. Ladd, T.B., Wolfe, M.S., and Golde, T.E., 2004. Signal peptide peptidase forms a homodimer that is labeled by an active site-directed gamma-secretase inhibitor. J Biol Chem 279: 15153–15160.PubMedCrossRefGoogle Scholar
  69. Oh, Y.S., and Turner, R.J., 2005. Topology of the C-terminal fragment of human presenilin 1. Biochemistry 44: 11821–11828.PubMedCrossRefGoogle Scholar
  70. Okochi, M. Fukumori, A. Jiang, J. Itoh, N. Kimura, R. Steiner, H. Haass, C. Tagami, S. and Takeda, M., 2006. Secretion of the Notch-1 Abeta-like peptide during Notch signaling. J Biol Chem 281: 7890–7898.PubMedCrossRefGoogle Scholar
  71. Okochi, M. Steiner, H. Fukumori, A. Tanii, H. Tomita, T. Tanaka, T. Iwatsubo, T. Kudo, T. Takeda, M., and Haass, C. 2002. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 21: 5408–5416.PubMedCrossRefGoogle Scholar
  72. Podlisny, M.B., Citron, M. Amarante, P. Sherrington, R. Xia, W. Zhang, J. Diehl, T. Levesque, G. Fraser, P. Haass, C. , et al., 1997. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis 3: 325–337.PubMedCrossRefGoogle Scholar
  73. Qi-Takahara, Y. Morishima-Kawashima, M. Tanimura, Y. Dolios, G. Hirotani, N. Horikoshi, Y. Kametani, F. Maeda, M. Saido, T.C., Wang, R. , et al., 2005. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci 25: 436–445.PubMedCrossRefGoogle Scholar
  74. Ratovitski, T. Slunt, H.H., Thinakaran, G. Price, D.L., Sisodia, S.S., and Borchelt, D.R., 1997. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem 272: 24536–24541.PubMedCrossRefGoogle Scholar
  75. Refolo, L.M., Eckman, C. Prada, C.M., Yager, D. Sambamurti, K. Mehta, N. Hardy, J. and Younkin, S.G., 1999. Antisense-induced reduction of presenilin 1 expression selectively increases the production of amyloid beta42 in transfected cells. J Neurochem 73: 2383–2388.PubMedCrossRefGoogle Scholar
  76. Rogaev, E.I., Sherrington, R. Rogaeva, E.A., Levesque, G. Ikeda, M. Liang, Y. Chi, H. Lin, C. 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.PubMedCrossRefGoogle Scholar
  77. Roher, A.E., Lowenson, J.D., Clarke, S. Woods, A.S., Cotter, R.J., Gowing, E. and Ball, M.J., 1993. beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A 90: 10836–10840.PubMedCrossRefGoogle Scholar
  78. Sato, T. Dohmae, N. Qi, Y. Kakuda, N. Misonou, H. Mitsumori, R. Maruyama, H. Koo, E.H., Haass, C. Takio, K. , et al., 2003. Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein. J Biol Chem 278: 24294–24301.PubMedCrossRefGoogle Scholar
  79. Sato, T. Nyborg, A.C., Iwata, N. Diehl, T.S., Saido, T.C., Golde, T.E., and Wolfe, M.S., Signal peptide peptidase: biochemical properties and modulation by nonsteroidal anti-inflammatory drugs. Biochemistry 45: 8649–8656.Google Scholar
  80. Sato, T. Tanimura, Y. Hirotani, N. Saido, T.C., Morishima-Kawashima, M. and Ihara, Y. 2005. Blocking the cleavage atmidportion between gamma- and epsilon-sites remarkably suppresses the generation of amyloid beta-protein. FEBS Lett 579: 2907–2912.PubMedCrossRefGoogle Scholar
  81. Saura, C.A., Choi, S.Y., Beglopoulos, V. Malkani, S. Zhang, D. Shankaranarayana Rao, B.S., Chattarji,S., Kelleher, R.J., 3rd, Kandel, E.R., 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.PubMedCrossRefGoogle Scholar
  82. Saura, C.A., Tomita, T. Soriano, S. Takahashi, M. Leem, J.Y., Honda, T. Koo, E.H., Iwatsubo, T. and Thinakaran, G. 2000. The nonconserved hydrophilic loop domain of presenilin (PS) is not required for PS endoproteolysis or enhanced abeta 42 production mediated by familial early onset alzheimer’s disease-linked PS variants. J Biol Chem 275: 17136–17142.PubMedCrossRefGoogle Scholar
  83. Scheuner, D. Eckman, C. Jensen, M. Song, X. Citron, M. Suzuki, N. Bird, T.D., Hardy, J. Hutton, M., Kukull, W. , et al., 1996. Secreted amyloid beta-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.PubMedCrossRefGoogle Scholar
  84. Schroeter, E.H., Ilagan, M.X., Brunkan, A.L., Hecimovic, S. Li, Y.M., Xu, M. Lewis, H.D., Saxena, M.T., De Strooper, B. Coonrod, A. , et al., 2003. A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci U S A 100: 13075–13080.PubMedCrossRefGoogle Scholar
  85. Schroeter, E.H., Kisslinger, J.A., and Kopan, R. 1998. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393: 382–386.PubMedCrossRefGoogle Scholar
  86. Searfoss, G.H., Jordan, W.H., Calligaro, D.O., Galbreath, E.J., Schirtzinger, L.M., Berridge, B.R., Gao, H., Higgins, M.A., May, P.C., and Ryan, T.P., 2003. Adipsin: a biomarker of gastrointestinal toxicity mediated by a functional gamma secretase inhibitor. J Biol Chem 29: 29.Google Scholar
  87. Seiffert, D. Bradley, J.D., Rominger, C.M., Rominger, D.H., Yang, F. Meredith, J.E., Jr., Wang, Q. Roach, A.H., Thompson, L.A., Spitz, S.M. , et al., 2000. Presenilin-1 and -2 are molecular targets for gamma -secretase inhibitors. J Biol Chem 275: 34086–34091.PubMedCrossRefGoogle Scholar
  88. Selkoe, D.J., 2001. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81: 741–766.PubMedGoogle Scholar
  89. Shah, S. Lee, S.F., Tabuchi, K. Hao, Y.H., Yu, C. LaPlant, Q. Ball, H. Dann, C.E., 3rd, Sudhof, T., and Yu, G. 2005. Nicastrin functions as a gamma-secretase-substrate receptor. Cell 122: 435–447.PubMedCrossRefGoogle Scholar
  90. Shearman, M.S., Beher, D. Clarke, E.E., Lewis, H.D., Harrison, T. Hunt, P. Nadin, A. Smith, A.L., Stevenson, G. and Castro, J.L., 2000. L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid beta-Protein Precursor gamma-Secretase Activity. Biochemistry 39: 8698–8704.PubMedCrossRefGoogle Scholar
  91. Shen, J. Bronson, R.T., Chen, D.F., Xia, W. Selkoe, D.J., and Tonegawa, S. 1997. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89: 629–639.PubMedCrossRefGoogle Scholar
  92. Sherrington, R. Rogaev, E.I., Liang, Y. Rogaeva, E.A., Levesque, G. Ikeda, M. Chi, H. Lin, C. 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.PubMedCrossRefGoogle Scholar
  93. Shirotani, K. Edbauer, D. Prokop, S. Haass, C. and Steiner, H. 2004. Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 279: 41340–41345.PubMedCrossRefGoogle Scholar
  94. Siemers, E.R., Quinn, J.F., Kaye, J. Farlow, M.R., Porsteinsson, A. Tariot, P. Zoulnouni, P. Galvin, J.E., Holtzman, D.M., Knopman, D.S. , et al., 2006. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66: 602–604.PubMedCrossRefGoogle Scholar
  95. Song, W. Nadeau, P. Yuan, M. Yang, X. Shen, J. and Yankner, B.A., 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 U S A 96: 6959–6963.PubMedCrossRefGoogle Scholar
  96. Suzuki, N. Cheung, T.T., Cai, X.D., Odaka, A. Otvos, L. Jr., Eckman, C. Golde, T.E., and Younkin, S.G., 1994. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264: 1336–1340.PubMedCrossRefGoogle Scholar
  97. Takasugi, N. Tomita, T. Hayashi, I. Tsuruoka, M. Niimura, M. Takahashi, Y. Thinakaran, G. and Iwatsubo, T. 2003. The role of presenilin cofactors in the gamma-secretase complex. Nature 422: 438–441.PubMedCrossRefGoogle Scholar
  98. Tanzi, R.E., and Bertram, L. 2005. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120: 545–555.PubMedCrossRefGoogle Scholar
  99. Thinakaran, G. Borchelt, D.R., Lee, M.K., Slunt, H.H., 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.PubMedCrossRefGoogle Scholar
  100. Thinakaran, G. Harris, C.L., Ratovitski, T. Davenport, F. Slunt, H.H., Price, D.L., Borchelt, D.R., and Sisodia, S.S., 1997. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem 272: 28415–28422.PubMedCrossRefGoogle Scholar
  101. Tolia, A. Chavez-Gutierrez, L. and De Strooper, B. 2006. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the gamma -secretase complex. J Biol Chem 281: 27633–27642.PubMedCrossRefGoogle Scholar
  102. Tomita, T. Katayama, R. Takikawa, R. and Iwatsubo, T. 2002. Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments. FEBS Lett 520: 117–121.PubMedCrossRefGoogle Scholar
  103. Tomita, T. Takikawa, R. Koyama, A. Morohashi, Y. Takasugi, N. Saido, T.C., Maruyama, K. and Iwatsubo, T. 1999. C terminus of presenilin is required for overproduction of amyloidogenic Abeta42 through stabilization and endoproteolysis of presenilin. J Neurosci 19: 10627–10634.PubMedGoogle Scholar
  104. Watanabe, N. Tomita, T. Sato, C. Kitamura, T. Morohashi, Y. and Iwatsubo, T. 2005. Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. J Biol Chem 280: 41967–41975.PubMedCrossRefGoogle Scholar
  105. Weggen, S. Eriksen, J.L., Das, P. Sagi, S.A., Wang, R. Pietrzik, C.U., Findlay, K.A., Smith, T.E., Murphy, M.P., Bulter, T. , et al., 2001. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414: 212–216.PubMedCrossRefGoogle Scholar
  106. Weggen, S. Eriksen, J.L., Sagi, S.A., Pietrzik, C.U., Ozols, V. Fauq, A. Golde, T.E., and Koo, E.H., 2003. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem 278: 31831–31837.PubMedCrossRefGoogle Scholar
  107. Weidemann, A. Eggert, S. Reinhard, F.B., Vogel, M. Paliga, K., Baier, G. Masters, C.L., Beyreuther, K., and Evin, G. 2002. A Novel var epsilon-Cleavage within the Transmembrane Domain of the Alzheimer Amyloid Precursor Protein Demonstrates Homology with Notch Processing. Biochemistry 41: 2825–2835.PubMedCrossRefGoogle Scholar
  108. Weihofen, A. Binns, K. Lemberg, M.K., Ashman, K. and Martoglio, B. 2002. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296: 2215–2218.PubMedCrossRefGoogle Scholar
  109. Wolfe, M.S., De Los Angeles, J. Miller, D.D., Xia, W. and Selkoe, D.J., 1999a. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer’s disease. Biochemistry 38: 11223–11230.CrossRefGoogle Scholar
  110. Wolfe, M.S., and Kopan, R. 2004. Intramembrane proteolysis: theme and variations. Science 305: 1119–1123.PubMedCrossRefGoogle Scholar
  111. Wolfe, M.S., Xia, W. Moore, C.L., Leatherwood, D.D., Ostaszewski, B. Donkor, I.O., and Selkoe, D.J., 1999b. Peptidomimetic probes and molecular modeling suggest Alzheimer’s γ-secretases are intramembrane-cleaving aspartyl proteases. Biochemistry 38: 4720–4727.CrossRefGoogle Scholar
  112. Wolfe, M.S., Xia, W. Ostaszewski, B.L., Diehl, T.S., Kimberly, W.T., and Selkoe, D.J., 1999c. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398: 513–517.CrossRefGoogle Scholar
  113. Wong, G.T., Manfra, D. Poulet, F.M., Zhang, Q. Josien, H. Bara, T. Engstrom, L. Pinzon-Ortiz, M. Fine, J.S., Lee, H.J. , et al., 2004. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279: 12876–12882.PubMedCrossRefGoogle Scholar
  114. Wong, P.C., Zheng, H. Chen, H. Becher, M.W., Sirinathsinghji, D.J., Trumbauer, M.E., Chen, H.Y., Price, D.L., Van der Ploeg, L.H., and Sisodia, S.S., 1997. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature textbf387: 288–292.CrossRefGoogle Scholar
  115. Yagishita, S. Morishima-Kawashima, M. Tanimura, Y. Ishiura, S. and Ihara, Y. 2006. DAPT-induced intracellular accumulations of longer amyloid beta-proteins: further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry 45: 3952–3960.PubMedCrossRefGoogle Scholar
  116. Yu, G. Chen, F. Levesque, G. Nishimura, M. Zhang, D.M., Levesque, L. Rogaeva, E. Xu, D. Liang, Y., Duthie, M. , et al., 1998. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J Biol Chem 273: 16470–16475.PubMedCrossRefGoogle Scholar
  117. Yu, G. Nishimura, M. Arawaka, S. Levitan, D. Zhang, L. Tandon, A. Song, Y.Q., Rogaeva, E. Chen, F., Kawarai, T. , et al., 2000. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407: 48–54.PubMedCrossRefGoogle Scholar
  118. Zhou, S. Zhou, H. Walian, P.J., and Jap, B.K., 2005. CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer’s disease amyloid beta-peptide production. Proc Natl Acad Sci USA 102: 7499–7504.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Michael S. Wolfe
    • 1
  1. 1.Center For Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations