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γ-Secretase as a Target for Alzheimer's Disease

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Pharmacological Mechanisms in Alzheimer's Therapeutics

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The two characteristic pathological features of Alzheimer’s disease (AD) found in the brain are extracellular amyloid plaques and intraneuronal fibrillary tangles, the former being composed primarily of the 4-kDa amyloid β-peptide (Aβ) and the latter containing paired helical filaments of the microtubule-associated protein tau (Hardy, Duff, Hardy, Perez-Tur, & Hutton, 1998). While dominant mutations in the tau gene can cause other forms of dementia (Lee, Goedert, & Trojanowski, 2001), missense mutations in the Aβ precursor protein (APP) alter Aβ production and cause familial early onset AD (Selkoe, 2001).

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References

  • Anderson, J.J., Holtz, G., Baskin, P. P., Turner, M., Rowe, B., Wang, B., et al. (2005). Reductions in beta-amyloid concentrations invivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897. Biochemical Pharmacology, 69, 689–698.

    Article  PubMed  CAS  Google Scholar 

  • Barten, D. M., Guss, V. L., Corsa, J.A., Loo, A., Hansel, S. B., Zheng, M., et al. (2004). Dynamics of beta-Amyloid Reductions in Brain, Cerebrospinal Fluid and Plasma of beta-Amyloid Precursor Protein Transgenic Mice Treated with a gamma-Secretase Inhibitor. The Journal of Pharmacology and Experimental Therapeutics, 27, 27.

    Google Scholar 

  • Beher, D., Clarke, E. E., Wrigley, J.D., Martin, A. C., Nadin, A., Churcher, I., et al. (2004). Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism. The Journal of Biological Chemistry, 279, 43419–43426.

    Article  PubMed  CAS  Google Scholar 

  • Best, J.D., Jay, M. T., Out, F., Ma, J., Nadin, A., Ellis, S., et al. (2005). Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3, 5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo[b, d]azepin-7-yl]-L-alaninamide]. The Journal of Pharmacology and Experimental Therapeutics, 313, 902–908.

    Article  PubMed  CAS  Google Scholar 

  • Bihel, F., Das, C., Bowman, M. J., & Wolfe, M. S. (2004). Discovery of a subnanomolar helical D-tridecapeptide inhibitor of γ-secretase. Journal of Medicinal Chemistry, 47, 3931–3933.

    Article  PubMed  CAS  Google Scholar 

  • Capell, A., Grunberg, J., Pesold, B., Diehlmann, A., Citron, M., Nixon, R., et al. (1998). The proteolytic fragments of the Alzheimer's disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex. The Journal of Biological Chemistry, 273, 3205–3211.

    Article  PubMed  CAS  Google Scholar 

  • Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., et al. (1997). Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Medicine, 3, 67–72.

    Article  PubMed  CAS  Google Scholar 

  • Das, C., Berezovska, O., Diehl, T. S., Genet, C., Buldyrev, I., Tsai, J.Y., et al. (2003). Designed helical peptides inhibit an intramembrane protease. Journal of the American Chemical Society, 125, 11794–11795.

    Article  PubMed  CAS  Google Scholar 

  • De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J.S., et al. (1999). A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature, 398, 518–522.

    Article  PubMed  CAS  Google Scholar 

  • De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., et al. (1998). Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature, 391, 387–390.

    Article  PubMed  CAS  Google Scholar 

  • Dovey, H. F., John, V., Anderson, J.P., Chen, L. Z., de Saint Andrieu, P., Fang, L. Y., et al. (2001). Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. Journal of Neurochemistry, 76, 173–181.

    Article  PubMed  CAS  Google Scholar 

  • Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C. M., Perez-tur, J., et al. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature, 383, 710–713.

    Article  PubMed  CAS  Google Scholar 

  • Edbauer, D., Winkler, E., Regula, J.T., Pesold, B., Steiner, H., & Haass, C. (2003). Reconstitution of gamma-secretase activity. Nature Cell Biology, 5, 486–488.

    Article  PubMed  CAS  Google Scholar 

  • Eriksen, J.L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., et al. (2003). NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 invivo. The Journal of Clinical Investigation, 112, 440–449.

    PubMed  CAS  Google Scholar 

  • Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Diehl, T. S., Moore, C. L., Tsai, J.Y., et al. (2000). Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nature Cell Biology, 2, 428–434.

    Article  PubMed  CAS  Google Scholar 

  • Esler, W. P., Kimberly, W. T., Ostaszewski, B. L., Ye, W., Diehl, T. S., Selkoe, D. J., et al. (2002). Activity-dependent isolation of the presenilin/γ-secretase complex reveals nicastrin and a g substrate. Proceedings of the National Academy of Sciences of the United States of America, 99, 2720–2725.

    Article  PubMed  CAS  Google Scholar 

  • Fraering, P. C., LaVoie, M. J., Ye, W., Ostaszewski, B. L., Kimberly, W. T., Selkoe, D. J., et al. (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.

    Article  PubMed  CAS  Google Scholar 

  • Fraering, P. C., Ye, W., Strub, J.M., Dolios, G., LaVoie, M. J., Ostaszewski, B. L., et al. (2004b). Purification and Characterization of the Human gamma-Secretase Complex. Biochemistry, 43, 9774–9789.

    Article  PubMed  CAS  Google Scholar 

  • Fraering, P. C., Ye, W., Lavoie, M. J., Ostaszewski, B. L., Selkoe, D. J., & Wolfe, M. S. (2005). gamma -Secretase substrate selectivity can be modulated directly via interaction with a nucleotide binding site. The Journal of Biological Chemistry, 280, 41987–41996.

    Article  PubMed  CAS  Google Scholar 

  • Francis, R., McGrath, G., Zhang, J., Ruddy, D. A., Sym, M., Apfeld, J., et al. (2002). aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Developmental Cell, 3, 85–97.

    Article  PubMed  CAS  Google Scholar 

  • Goutte, C., Tsunozaki, M., Hale, V. A., & Priess, J.R. (2002). APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proceedings of the National Academy of Sciences of the United States of America, 99, 775–779.

    Article  PubMed  CAS  Google Scholar 

  • Hardy, J., Duff, K., Hardy, K. G., Perez-Tur, J., & Hutton, M. (1998). Genetic dissection of Alzheimer's disease and related dementias: Amyloid and its relationship to tau. Nature Neuroscience, 1, 355–358.

    Article  PubMed  CAS  Google Scholar 

  • Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science, 297, 353–356.

    Article  PubMed  CAS  Google Scholar 

  • Herreman, A., Serneels, L., Annaert, W., Collen, D., Schoonjans, L., & De Strooper, B. (2000). Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nature Cell Biology, 2, 461–462.

    Article  PubMed  CAS  Google Scholar 

  • Hu, Y., & Fortini, M. E. (2003). Different cofactor activities in gamma-secretase assembly: Evidence for a nicastrin-Aph-1 subcomplex. The Journal of Cell Biology, 161, 685–690.

    Article  PubMed  CAS  Google Scholar 

  • Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., & 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.

    Article  PubMed  CAS  Google Scholar 

  • Jarrett, J.T., Berger, E. P., & Lansbury, P. T., Jr. (1993). The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease. Biochemistry, 32, 4693–4697.

    Article  PubMed  CAS  Google Scholar 

  • Kim, S. H., & Sisodia, S. S. (2005). Evidence that the “NF” motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. The Journal of Biological Chemistry, 280, 41953–41966.

    Article  PubMed  CAS  Google Scholar 

  • Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., & Selkoe, D. J. (2003). γ-secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2. Proceedings of the National Academy of Sciences of the United States of America, 100, 6382–6387.

    Article  PubMed  CAS  Google Scholar 

  • Kopan, R., & Ilagan, M. X. (2004). Gamma-secretase: Proteasome of the membrane? Nature Reviews. Molecular Cell Biology, 5, 499–504.

    Article  PubMed  CAS  Google Scholar 

  • Kornilova, A. Y., Bihel, F., Das, C., & Wolfe, M. S. (2005). The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. Proceedings of the National Academy of Sciences of the United States of America, 102, 3230–3235.

    Article  PubMed  CAS  Google Scholar 

  • Kornilova, A. Y., Das, C., & Wolfe, M. S. (2003). Differential effects of inhibitors on the gamma-secretase complex. Mechanistic implications. The Journal of Biological Chemistry, 278, 16470–16473.

    Article  PubMed  CAS  Google Scholar 

  • Lanz, T. A., Himes, C. S., Pallante, G., Adams, L., Yamazaki, S., Amore, B., et al. (2003). The gamma-secretase inhibitor N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces A beta levels invivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. The Journal of Pharmacology and Experimental Therapeutics, 305, 864–871.

    Article  PubMed  CAS  Google Scholar 

  • LaVoie, M. J., Fraering, P. C., Ostaszewski, B. L., Ye, W., Kimberly, W. T., Wolfe, M. S., et al. (2003). Assembly of the {gamma}-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and Nicastrin. The Journal of Biological Chemistry, 278, 37213–37222.

    Article  PubMed  CAS  Google Scholar 

  • Lee, V. M., Goedert, M., & Trojanowski, J.Q. (2001). Neurodegenerative tauopathies. Annual Review of Neuroscience, 24, 1121–1159.

    Article  PubMed  CAS  Google Scholar 

  • Lemere, C. A., Lopera, F., Kosik, K. S., Lendon, C. L., Ossa, J., Saido, T. C., et al. (1996). The E280A presenilin 1 Alzheimer mutation produces increased A-beta 42 deposition and severe cerebellar pathology. Nature Medicine, 2, 1146–1150.

    Article  PubMed  CAS  Google Scholar 

  • Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, 269, 973–977.

    Article  PubMed  CAS  Google Scholar 

  • Li, Y. M., Xu, M., Lai, M. T., Huang, Q., Castro, J.L., DiMuzio-Mower, J., et al. (2000). Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature, 405, 689–694.

    Article  PubMed  CAS  Google Scholar 

  • Morais, V. A., Crystal, A. S., Pijak, D. S., Carlin, D., Costa, J., Lee, V. M., et al. (2003). The transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex. The Journal of Biological Chemistry, 278, 43284–43291.

    Article  PubMed  CAS  Google Scholar 

  • Netzer, W. J., Dou, F., Cai, D., Veach, D., Jean, S., Li, Y., et al. (2003). Gleevec inhibits beta-amyloid production but not Notch cleavage. Proceedings of the National Academy of Sciences of the United States of America, 100, 12444–12449.

    Article  PubMed  CAS  Google Scholar 

  • Okochi, M., Fukumori, A., Jiang, J., Itoh, N., Kimura, R., Steiner, H., et al. (2006). Secretion of the Notch-1 Abeta-like peptide during Notch signaling. The Journal of Biological Chemistry, 281, 7890–7898.

    Article  PubMed  CAS  Google Scholar 

  • Ratovitski, T., Slunt, H. H., Thinakaran, G., Price, D. L., Sisodia, S. S., & Borchelt, D. R. (1997). Endoproteolytic processing and stabilization of wild-type and mutant presenilin. The Journal of Biological Chemistry, 272, 24536–24541.

    Article  PubMed  CAS  Google Scholar 

  • Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., 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.

    Article  PubMed  CAS  Google Scholar 

  • Sato, T., Nyborg, A. C., Iwata, N., Diehl, T. S., Saido, T. C., Golde, T. E., et al. (2006). Signal peptide peptidase: Biochemical properties and modulation by nonsteroidal anti-inflammatory drugs. Biochemistry, 45, 8649–8656.

    Article  PubMed  CAS  Google Scholar 

  • Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., et al. (1996). Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased invivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Medicine, 2, 864–870.

    Article  PubMed  CAS  Google Scholar 

  • Schroeter, E. H., Kisslinger, J.A., & Kopan, R. (1998). Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature, 393, 382–386.

    Article  PubMed  CAS  Google Scholar 

  • Searfoss, G. H., Jordan, W. H., Calligaro, D. O., Galbreath, E. J., Schirtzinger, L. M., Berridge, B. R., et al. (2003). Adipsin: A biomarker of gastrointestinal toxicity mediated by a functional gamma secretase inhibitor. The Journal of Biological Chemistry, 29, 29.

    Google Scholar 

  • Selkoe, D. J. (2001). Alzheimer's disease: Genes, proteins, and therapy. Physiological Reviews, 81, 741–766.

    PubMed  CAS  Google Scholar 

  • Selkoe, D. J., & Kopan, R. (2003). Notch and Presenilin: Regulated intramembrane proteolysis links development and degeneration. Annual Review of Neuroscience, 26, 565–597.

    Article  PubMed  CAS  Google Scholar 

  • Shah, S., Lee, S. F., Tabuchi, K., Hao, Y. H., Yu, C., LaPlant, Q., et al. (2005). Nicastrin functions as a gamma-secretase-substrate receptor. Cell, 122, 435–447.

    Article  PubMed  CAS  Google Scholar 

  • Shen, J., Bronson, R. T., Chen, D. F., Xia, W., Selkoe, D. J., & Tonegawa, S. (1997). Skelet al and CNS defects in Presenilin-1-deficient mice. Cell, 89, 629–639.

    Article  PubMed  CAS  Google Scholar 

  • Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature, 375, 754–760.

    Article  PubMed  CAS  Google Scholar 

  • Shirotani, K., Edbauer, D., Kostka, M., Steiner, H., & Haass, C. (2004). Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: Identification of nicastrin mutants that selectively interact with APH-1. Journal of Neurochemistry, 89, 1520–1527.

    Article  PubMed  CAS  Google Scholar 

  • Siemers, E., Skinner, M., Dean, R. A., Gonzales, C., Satterwhite, J., Farlow, M., et al. (2005). Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clinical Neuropharmacology, 28, 126–132.

    Article  PubMed  CAS  Google Scholar 

  • Siemers, E. R., Quinn, J.F., Kaye, J., Farlow, M. R., Porsteinsson, A., Tariot, P., et al. (2006). Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology, 66, 602–604.

    Article  PubMed  CAS  Google Scholar 

  • Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., et al. (2003). The role of presenilin cofactors in the gamma-secretase complex. Nature, 422, 438–441.

    Article  PubMed  CAS  Google Scholar 

  • Thinakaran, G., Borchelt, D. R., Lee, M. K., Slunt, H. H., Spitzer, L., Kim, G., et al. (1996). Endoproteolysis of presenilin 1 and accumulation of processed derivatives invivo. Neuron, 17, 181–190.

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, N., Tomita, T., Sato, C., Kitamura, T., Morohashi, Y., & Iwatsubo, T. (2005). Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. The Journal of Biological Chemistry, 280, 41967–41975.

    Article  PubMed  CAS  Google Scholar 

  • Weggen, S., Eriksen, J.L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., et al. (2001). A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 414, 212–216.

    Article  PubMed  CAS  Google Scholar 

  • Weggen, S., Eriksen, J.L., Sagi, S. A., Pietrzik, C. U., Ozols, V., Fauq, A., et al. (2003). Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. The Journal of Biological Chemistry, 278, 31831–31837.

    Article  PubMed  CAS  Google Scholar 

  • Weihofen, A., Binns, K., Lemberg, M. K., Ashman, K., & Martoglio, B. (2002). Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science, 296, 2215–2218.

    Article  PubMed  CAS  Google Scholar 

  • Wolfe, M. S., De Los Angeles, J., Miller, D. D., Xia, W., & Selkoe, D. J. (1999). Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease. Biochemistry, 38, 11223–11230.

    Article  PubMed  CAS  Google Scholar 

  • Wolfe, M. S., Xia, W., Moore, C. L., Leatherwood, D. D., Ostaszewski, B., Donkor, I. O., et al. (1999). Peptidomimetic probes and molecular modeling suggest Alzheimer's γ-secretases are intramembrane-cleaving aspartyl proteases. Biochemistry, 38, 4720–4727.

    Article  PubMed  CAS  Google Scholar 

  • Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., & Selkoe, D. J. (1999). Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature, 398, 513–517.

    Article  PubMed  CAS  Google Scholar 

  • Wong, G. T., Manfra, D., Poulet, F. M., Zhang, Q., Josien, H., Bara, T., 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. The Journal of Biological Chemistry, 279, 12876–12882.

    Article  PubMed  CAS  Google Scholar 

  • Wong, P. C., Zheng, H., Chen, H., Becher, M. W., Sirinathsinghji, D. J., Trumbauer, M. E., et al. (1997). Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature, 387, 288–292.

    Article  PubMed  CAS  Google Scholar 

  • Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., et al. (2000). Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature, 407, 48–54.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Z., Nadeau, P., Song, W., Donoviel, D., Yuan, M., Bernstein, A., et al. (2000). Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nature Cell Biology, 2, 463–465.

    Article  PubMed  CAS  Google Scholar 

  • Zhou, S., Zhou, H., Walian, P. J., & Jap, B. K. (2005). CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production. Proceedings of the National Academy of Sciences of the United States of America, 102, 7499–7504.

    Article  PubMed  CAS  Google Scholar 

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  1. Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA

    Michael S. Wolfe

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Wolfe, M.S. (2007). γ-Secretase as a Target for Alzheimer's Disease. In: Pharmacological Mechanisms in Alzheimer's Therapeutics. Springer, New York, NY. https://doi.org/10.1007/978-0-387-71522-3_8

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