Gamma secretase

AD A22 A22.001 Presen ilin 1 Gamma-secretase of Alzheimer s disease, and a drug target... 

The enzymes that are involved in the processing of APP into amyloid peptides are known as secretases. Beta-secretase is an enzyme that catalyzes the initial proteolytic event leading to the production of Abeta amyloid peptides. If APP is cleaved by beta-secretase it can then be further cleaved by gamma-secretase. Abeta peptides are either secreted or intracellularly released. They have varying lengths and represent intermediate degradation products of its precursor (i.e., (3-secretase cleaved APP). Especially the 42 amino acid peptide (A 342) aggregates to form insoluble amyloid plaques. 

Zhang, D., Hanson, R., Roongta, V. et al. (2006) In vitro and in vivo metabolism of a gamma-secretase inhibitor BMS-299897 and generation of active metabolites in milligram quantities with a microbial bioreactor. Current Drug Metabolism, 7, 883-896. 

Table 2 Effects of fluorine on the properties of gamma-secretase inhibitors... 

Lundberg, P. and Langel, U. (2006). Uptake mechanisms of cell-penetrating peptides derived from the Alzheimer s disease associated gamma-secretase complex. Int. J. Pept. Res. Therap. 12, 105-114. 

Fortini, M. E. (2002). Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat. Rev. Mol. Cell Biol. 3, 673-84. 

Berezovska, O., Jack, C., McLean, P., Aster, J. C., Hicks, C., Xia, W., Wolfe, M. S., Weinmaster, G., Selkoe, D. J. and Hyman, B. T. (2000). Rapid Notch 1 nuclear translocation after ligand binding depends on presenilin-associated gamma-secretase activity. Ann. N.Y. Acad. Sci. 

DTBP also has been used to investigate the dimerization and actin bundling properties of vil-lin (George et al., 2007), the interaction of the Mrell complex with RPA (Olson et al., 2007), the study of gamma-secretase complex assembly (Spasic et al., 2007), and the multi-protein assembly of Kv4.2, KChIP3 and DPP10 (Jerng et al., 2005). 

De Strooper, B. Aph-1, Pen-2, and nicastrin with presenilin generate an active gamma-secretase complex. Neuron 38 9-12, 2003. 

Takasugi, N., Tomita, T., Hayashi, I. et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 422 438M41,2003. 

Haass, C. Take five—BACE and the gamma-secretase quartet conduct Alzheimer s amyloid beta-peptide generation. EMBO J. 23 483-488, 2004. 

Iwatsubo, T. The gamma-secretase complex machinery for intramembrane proteolysis. Curr. Opin. Neurobiol. 14 379-383, 2004. 

Li, T., Ma, G., Cai, H. etal. 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. /. Neurosci. 23 3272-3277, 2003. 

Steiner, H., Winkler, E., Edbauer, D. et al. PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. /. Biol. Chem. 277 39062-39065, 2002. 

Esler,W. P.,Kimberly,W.T.,Ostaszewski,B. L. etal.Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nature Cell Biol. 2 428-434,2000. 

De Strooper, B., Annaert, W. G., Cupers, P. et al. A presenilin-1 -dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398 518-522,1999. 

Weggen, S., Eriksen, J.L., Sagi, S.A., Pietrzik, C.U., Ozols, V., Fauq, A., Golde, T.E., and Koo, E.H., Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity, /. Biol. Chem., 278, 31831, 2003. 

Jankowski, J.L., Fadale, D.J., Anderson, J., et al. (2004) Mutant preseniUns specifically elevate the levels of the 42 residue beta-amyloid peptide in vitro evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet., 13, 159-170. 

Gupta-Rossi, N., Six, E., LeBail, O., et al. (2004) Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J. Cell Biol., 166, 73-83. 

Okochi, M., Steiner, H., Fukimoii, A., et al. (2002) Presenihns mediate a dual intramembra-nous gamma-secretase cleavage of Notch-1. EMBO J., 21, 5408-5416. 

Francis, R., McGrath, G., Zhang, G., et al. (2002) Aph-1 and pen-2 are required for Notch pathway signalhng, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation. Dev. Cell, 3, 85-97. 

Beher, D., Flicker, M., Nadin, A., et al. (2003) In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand. Biochemistry, 42, 8133-8142. 

Pitsi, D., Octave, J.N. (2004) Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gamma-secretase activity. J. Biol. Chem., 279,... 

Massey, L.K., Mah, A.L., Monteiro, M.J. (2005) Ubiquilin regulates presenihn endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. Biochem. J., 391, 513-525. 

Dovey, H.F., John, V., Anderson, J.P., et al. (2001) Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem., 76, 173-181. 

Wahrle, S., Das, P., Nyborg, A.C., et al. (2002) Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis., 9, 11-23. 

Vetrivel, K.S., Cheng, H., Lin, W., et al. (2004) Association of gamma-secretase with Upid rafts in post-Golgi and endosome membranes. J. Biol. Chem., 279, 44945-44954. 

He G, Luo W, Li P et al (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer s disease. Nature 467 95-98... 

Beher, D. (2008). Gamma-secretase modulation and its promise for Alzheimer s disease a rationale for drug discovery. Current Topics in Medicinal Chemistry 8, 34—37. 

Sisodia, S.S. and St George-Hyslop, P.H. (2002) Gamma-Secretase, Notch, Abeta and Alzheimer s disease where do the presenilins fit in Nat. Rev. Neurosci. 3, 281-290. 

Li YM, Xu M, Lai MT et al (2000) Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405 689-694... 

---