The γ-secretase complex: From structure to function

Frontiers in Cellular Neuroscience

Volumn 8, Issue DEC, 2014, Pages

  Zhang, Xian ^a   Li, Yanfang ^a   Xu, Huaxi ^a,b   Zhang, Yun Wu ^a  

^a XIAMEN UNIVERSITY   (China)

^b BURNHAM INSTITUTE   (United States)

Author keywords

Alzheimer s disease; Anterior pharynx defective 1; Nicastrin; Presenilin; Presenilin enhancer 2; secretase

Indexed keywords

AMYLOID PRECURSOR PROTEIN; ANTERIOR PHARYNX DEFECTIVE 1 PROTEIN; ANTIINFLAMMATORY AGENT; BETA SECRETASE; CD147 ANTIGEN; CD82 ANTIGEN; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 4; GAMMA SECRETASE; HERMES ANTIGEN; IMATINIB; INOSITOL 1, 4, 5 TRISPHOSPHATE RECEPTOR; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN; MEMBRANE METALLOENDOPEPTIDASE; MEMBRANE PROTEIN; MEMBRANE RECEPTOR; MONOPHENOL MONOOXYGENASE; NICASTRIN; PRESENILIN 2; PROTEIN P53; PROTEIN PS2; RYANODINE RECEPTOR; TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; APOPTOSIS; AUTOPHAGY; BIOLOGICAL FUNCTIONS; BRAIN; CAENORHABDITIS ELEGANS; CARCINOGENESIS; CELL DIFFERENTIATION; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CHROMOSOME 1; CHROMOSOME 14; DOWN REGULATION; ELECTRON MICROSCOPY; ENDOPLASMIC RETICULUM; GENE DELETION; GENE MUTATION; GENETIC SCREENING; GENETIC TRANSCRIPTION; HAIR DISEASE; HEK293 CELL LINE; HUMAN; LINKAGE ANALYSIS; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN ASSEMBLY; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SKIN DEFECT; TRANS GOLGI NETWORK; TRANSACTIVATION;

EID: 84917741466     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2014.00427     Document Type: Review

References (195)

1. Acx, H., Chávez-Gutiérrez, L., Serneels, L., Lismont, S., Benurwar, M., Elad, N., et al. (2014). Signature amyloid beta profiles are produced by different gamma-secretase complexes. J. Biol. Chem. 289, 4346-4355. doi: 10.1074/jbc.m113.530907
2. Ahn, K., Shelton, C. C., Tian, Y., Zhang, X., Gilchrist, M. L., Sisodia, S. S., et al. (2010). Activation and intrinsic gamma-secretase activity of presenilin 1. Proc. Natl. Acad. Sci. U S A 107, 21435-21440. doi: 10.1073/pnas.1013246107
3. Andersson, E. R., Sandberg, R., and Lendahl, U. (2011). Notch signaling: simplicity in design, versatility in function.Development 138, 3593-3612. doi: 10.1242/dev.063610
4. Baek, S. H., Ohgi, K. A., Rose, D. W., Koo, E. H., Glass, C. K., and Rosenfeld, M. G. (2002). Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Cell 110, 55-67. doi: 10.1016/s0092-8674(02)00809-7
5. Baumann, K., Paganetti, P. A., Sturchler-Pierrat, C., Wong, C., Hartmann, H., Cescato, R., et al. (1997). Distinct processing of endogenous and overexpressed recombinant presenilin 1. Neurobiol. Aging 18, 181-189. doi: 10.1016/s0197-4580(97)00004-3
6. Bergman, A., Hansson, E. M., Pursglove, S. E., Farmery, M. R., Lannfelt, L., Lendahl, U., et al. (2004). Pen-2 is sequestered in the endoplasmic reticulum and subjected to ubiquitylation and proteasome-mediated degradation in the absence of presenilin. J. Biol. Chem. 279, 16744-16753. doi: 10.1074/jbc.m313999200
7. Bezprozvanny, I., and Hiesinger, P. R. (2013). The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol. Neurodegener. 8:23. doi: 10.1186/1750-1326-8-23
8. Bolduc, D. M., and Wolfe, M. S. (2014). Structure of nicastrin unveils secrets of gamma-secretase. Proc. Natl. Acad. Sci. U S A 111, 14643-14644. doi: 10.1073/pnas.1416637111
9. Borchelt, D. R., Ratovitski, T., van Lare, J., Lee, M. K., Gonzales, V., Jenkins, N. A., et al. (1997). Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939-945. doi: 10.1016/s0896-6273(00)80974-5
10. Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., et al. (1996). Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005-1013. doi: 10.1016/s0896-6273(00)80230-5
11. Borgegard, T., Juréus, A., Olsson, F., Rosqvist, S., Sabirsh, A., Rotticci, D., et al. (2012). First and second generation gamma-secretase modulators (GSMs) modulate amyloid-beta (Abeta) peptide production through different mechanisms. J. Biol. Chem. 287, 11810-11819. doi: 10.1074/jbc.m111.305227
12. Brown, M. S., Ye, J., Rawson, R. B., and Goldstein, J. L. (2000). Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391-398. doi: 10.1016/s0092-8674(00)80675-3
13. Cai, D., Leem, J. Y., Greenfield, J. P., Wang, P., Kim, B. S., Wang, R., et al. (2003). Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein. J. Biol. Chem. 278, 3446-3454. doi: 10.1074/jbc.m209065200
14. Capell, A., Beher, D., Prokop, S., Steiner, H., Kaether, C., Shearman, M. S., et al. (2005). Gamma-secretase complex assembly within the early secretory pathway. J. Biol. Chem. 280, 6471-6478. doi: 10.1074/jbc.m409106200
15. Capell, A., Grünberg, 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. J. Biol. Chem. 273, 3205-3211. doi: 10.1074/jbc.273.6.3205
16. Chami, L., and Checler, F. (2012). BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer's disease. Mol. Neurodegener. 7:52. doi: 10.1186/1750-1326-7-52
17. Chen, A. C., Guo, L. Y., Ostaszewski, B. L., Selkoe, D. J., and LaVoie, M. J. (2010). Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates. J. Biol. Chem. 285, 11378-11391. doi: 10.1074/jbc.m109.088815
18. Chen, F., Hasegawa, H., Schmitt-Ulms, G., Kawarai, T., Bohm, C., Katayama, T., et al. (2006). TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 440, 1208-1212. doi: 10.1038/nature04667
19. Chen, G. J., Xiong, Z., and Yan, Z. (2013). Abeta impairs nicotinic regulation of inhibitory synaptic transmission and interneuron excitability in prefrontal cortex. Mol. Neurodegener. 8:3. doi: 10.1186/1750-1326-8-3
20. Cheung, K. H., Shineman, D., Müller, M., Cárdenas, C., Mei, L., Yang, J., et al. (2008). Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58, 871-883. doi: 10.1016/j.neuron.2008.04.015
21. Chu, J., Lauretti, E., Craige, C. P., and Pratico, D. (2014). Pharmacological modulation of GSAP reduces amyloid-beta levels and tau phosphorylation in a mouse model of Alzheimer's disease with plaques and tangles. J. Alzheimers Dis. 41, 729-737. doi: 10.3233/JAD-140105
22. 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. Nat. Med. 3, 67-72. doi: 10.1038/nm0197-67
23. Conlon, R. A., Reaume, A. G., and Rossant, J. (1995). Notch1 is required for the coordinate segmentation of somites. Development 121, 1533-1545.
24. Crump, C. J., Johnson, D. S., and Li, Y. M. (2013). Development and mechanism of gamma-secretase modulators for Alzheimer's disease. Biochemistry 52, 3197-3216. doi: 10.1021/bi400377p
25. Crystal, A. S., Morais, V. A., Fortna, R. R., Carlin, D., Pierson, T. C., Wilson, C. A., et al. (2004). Presenilin modulates Pen-2 levels posttranslationally by protecting it from proteasomal degradation. Biochemistry 43, 3555-3563. doi: 10.1021/bi0361214
26. Crystal, A. S., Morais, V. A., Pierson, T. C., Pijak, D. S., Carlin, D., Lee, V. M., et al. (2003). Membrane topology of gamma-secretase component PEN-2. J. Biol. Chem. 278, 20117-20123. doi: 10.1074/jbc.m213107200
27. Culvenor, J. G., Ilaya, N. T., Ryan, M. T., Canterford, L., Hoke, D. E., Williamson, N. A., et al. (2004). Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations. Eur. J. Biochem. 271, 375-385. doi: 10.1046/j.1432-1033.2003.03936.x
28. Del Prete, D., Checler, F., and Chami, M. (2014). Ryanodine receptors: physiological function and deregulation in Alzheimer disease. Mol. Neurodegener. 9:21. doi: 10.1186/1750-1326-9-21
29. De Strooper, B. (2003). Aph-1, Pen-2 and Nicastrin with Presenilin generate an active gamma-Secretase complex.Neuron 38, 9-12. doi: 10.1016/s0896-6273(03)00205-8
30. De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., et al. (1999). A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518-522. doi: 10.1038/19083
31. De Strooper, B., Iwatsubo, T., and Wolfe, M. S. (2012). Presenilins and gamma-secretase: structure, function and role in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a006304. doi: 10.1101/cshperspect.a006304
32. 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. doi: 10.1038/34910
33. Doan, A., Thinakaran, G., Borchelt, D. R., Slunt, H. H., Ratovitsky, T., Podlisny, M., et al. (1996). Protein topology of presenilin 1. Neuron 17, 1023-1030. doi: 10.1016/S0896-6273(00)80232-9
34. Doerfler, P., Shearman, M. S., and Perlmutter, R. M. (2001). Presenilin-dependent gamma-secretase activity modulates thymocyte development. Proc. Natl. Acad. Sci. U S A 98, 9312-9317. doi: 10.1073/pnas.161102498
35. Donoviel, D. B., Hadjantonakis, A. K., Ikeda, M., Zheng, H., Hyslop, P. S., and Bernstein, A. (1999). Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13, 2801-2810. doi: 10.1101/gad.13.21.2801
36. Doody, R. S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., et al. (2013). A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369, 341-350. doi: 10.1056/NEJMoa1210951
37. Dries, D. R., Shah, S., Han, Y. H., Yu, C., Yu, S., Shearman, M. S., et al. (2009). Glu-333 of nicastrin directly participates in gamma-secretase activity. J. Biol. Chem. 284, 29714-29724. doi: 10.1074/jbc.m109.038737
38. 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. doi: 10.1038/383710a0
39. Dunys, J., Kawarai, T., Sevalle, J., Dolcini, V., George-Hyslop, P. S., Da Costa, C. A., et al. (2007). p53-Dependent Aph-1 and Pen-2 anti-apoptotic phenotype requires the integrity of the gamma-secretase complex but is independent of its activity. J. Biol. Chem. 282, 10516-10525. doi: 10.1074/jbc.m611572200
40. Eimer, W. A., and Vassar, R. (2013). Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation. Mol. Neurodegener. 8:2. doi: 10.1186/1750-1326-8-2
41. 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 gamma-secretase bind directly to presenilin-1. Nat. Cell Biol. 2, 428-434. doi: 10.1038/35017062
42. Flood, D. G., Reaume, A. G., Dorfman, K. S., Lin, Y. G., Lang, D. M., Trusko, S. P., et al. (2002). FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction. Neurobiol. Aging 23, 335-348. doi: 10.1016/s0197-4580(01)00330-x
43. Fortna, R. R., Crystal, A. S., Morais, V. A., Pijak, D. S., Lee, V. M., and Doms, R. W. (2004). Membrane topology and nicastrin-enhanced endoproteolysis of APH-1, a component of the gamma-secretase complex. J. Biol. Chem. 279, 3685-3693. doi: 10.1074/jbc.m310505200
44. 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. Dev. Cell 3, 85-97. doi: 10.1016/S1534-5807(02)00189-2
45. Fukumori, A., Fluhrer, R., Steiner, H., and Haass, C. (2010). Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis. J. Neurosci. 30, 7853-7862. doi: 10.1523/jneurosci.1443-10.2010
46. Giliberto, L., Zhou, D., Weldon, R., Tamagno, E., De Luca, P., Tabaton, M., et al. (2008). Evidence that the Amyloid beta Precursor Protein-intracellular domain lowers the stress threshold of neurons and has a "regulated" transcriptional role. Mol. Neurodegener. 3:12. doi: 10.1186/1750-1326-3-12
47. 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. Commun. 120, 885-890. doi: 10.1016/S0006-291X(84)80190-4
48. Goate, A., Chartier-Harlin, M. C., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706. doi: 10.1038/349704a0
49. Golde, T. E. (2005). The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol. 15, 84-87. doi: 10.1111/j.1750-3639.2005.tb00104.x
50. Golde, T. E., Koo, E. H., Felsenstein, K. M., Osborne, B. A., and Miele, L. (2013). gamma-Secretase inhibitors and modulators. Biochim. Biophys. Acta 1828, 2898-2907. doi: 10.1016/j.bbamem.2013.06.005
51. 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.
52. Goutte, C., Tsunozaki, M., Hale, V. A., and Priess, J. R. (2002). APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc. Natl. Acad. Sci. U S A 99, 775-779. doi: 10.1073/pnas.022523499
53. Green, R. C., Schneider, L. S., Amato, D. A., Beelen, A. P., Wilcock, G., Swabb, E. A., et al. (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. doi: 10.1001/jama.2009.1866
54. Greenfield, J. P., Gross, R. S., Gouras, G. K., and Xu, H. (2000). Cellular and molecular basis of beta-amyloid precursor protein metabolism. Front. Biosci. 5, D72-D83. doi: 10.2741/greenfield
55. Grunberg, J., Walter, J., Loetscher, H., Deuschle, U., Jacobsen, H., and Haass, C. (1998). Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the caspase family. Biochemistry 37, 2263-2270. doi: 10.1021/bi972106l
56. Haapasalo, A., and Kovacs, D. M. (2011). The many substrates of presenilin/gamma-secretase. J. Alzheimers Dis.25, 3-28. doi: 10.3233/JAD-2011-101065
57. Haass, C., and De Strooper, B. (1999). The presenilins in Alzheimer's disease-proteolysis holds the key. Science286, 916-919. doi: 10.1126/science.286.5441.916
58. Haass, C., Kaether, C., Thinakaran, G., and Sisodia, S. (2012). Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2:a006270. doi: 10.1101/cshperspect.a006270
59. Haass, C., and Selkoe, D. J. (1993). Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75, 1039-1042. doi: 10.1016/0092-8674(93)90312-e
60. Hadland, B. K., Manley, N. R., Su, D., Longmore, G. D., Moore, C. L., Wolfe, M. S., et al. (2001). Gamma -secretase inhibitors repress thymocyte development. Proc. Natl. Acad. Sci. U S A 98, 7487-7491. doi: 10.1073/pnas.131202798
61. Hata, S., Taniguchi, M., Piao, Y., Ikeuchi, T., Fagan, A. M., Holtzman, D. M., et al. (2012). Multiple gamma-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects. Mol. Neurodegener. 7:16. doi: 10.1186/1750-1326-7-16
62. Hawkins, J., Harrison, D. C., Ahmed, S., Davis, R. P., Chapman, T., Marshall, I., et al. (2011). Dynamics of Abeta42 reduction in plasma, CSF and brain of rats treated with the gamma-secretase modulator, GSM-10h. Neurodegener. Dis. 8, 455-464. doi: 10.1159/000324511
63. Hayrapetyan, V., Rybalchenko, V., Rybalchenko, N., and 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. doi: 10.1016/j.ceca.2008.03.004
64. He, G., Luo, W., Li, P., Remmers, C., Netzer, W. J., Hendrick, J., et al. (2010). Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 467, 95-98. doi: 10.1038/nature09325
65. Hébert, S. S., Serneels, L., Dejaegere, T., Horré, K., Dabrowski, M., Baert, V., et al. (2004). Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol. Dis.17, 260-272. doi: 10.1016/j.nbd.2004.08.002
66. Hubbs, J. L., Fuller, N. O., Austin, W. F., Shen, R., Creaser, S. P., McKee, T. D., et al. (2012). Optimization of a natural product-based class of gamma-secretase modulators. J. Med. Chem. 55, 9270-9282. doi: 10.1021/jm300976b
67. Huppert, S. S., Le, A., Schroeter, E. H., Mumm, J. S., Saxena, M. T., Milner, L. A., et al. (2000). Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 405, 966-970. doi: 10.1038/35016111
68. Hussain, I., Fabrègue, J., Anderes, L., Ousson, S., Borlat, F., Eligert, V., et al. (2013). The role of gamma-secretase activating protein (GSAP) and imatinib in the regulation of gamma-secretase activity and amyloid-beta generation.J. Biol. Chem. 288, 2521-2531. doi: 10.1074/jbc.m112.370924
69. Imbimbo, B. P., Panza, F., Frisardi, V., Solfrizzi, V., D'onofrio, G., Logroscino, G., et al. (2011). Therapeutic intervention for Alzheimer's disease with gamma-secretase inhibitors: still a viable option? Expert Opin. Investig. Drugs 20, 325-341. doi: 10.1517/13543784.2011.550572
70. Iwatsubo, T. (2004). The gamma-secretase complex: machinery for intramembrane proteolysis. Curr. Opin. Neurobiol. 14, 379-383. doi: 10.1016/s0959-4388(04)00077-7
71. Jiang, S., Li, Y., Zhang, X., Bu, G., Xu, H., and Zhang, Y. W. (2014). Trafficking regulation of proteins in Alzheimer's disease. Mol. Neurodegener. 9:6. doi: 10.1186/1750-1326-9-6
72. Kaether, C., Capell, A., Edbauer, D., Winkler, E., Novak, B., Steiner, H., et al. (2004). The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J. 23, 4738-4748. doi: 10.1038/sj.emboj.7600478
73. Kang, D. E., Yoon, I. S., Repetto, E., Busse, T., Yermian, N., Ie, L., et al. (2005). Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J. Biol. Chem. 280, 31537-31547. doi: 10.1074/jbc.m500833200
74. Kim, H. S., Kim, E. M., Lee, J. P., Park, C. H., Kim, S., Seo, J. H., et al. (2003). C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3beta expression. FASEB J. 17, 1951-1953. doi: 10.1096/fj.03-0106fje
75. Kim, J., and Schekman, R. (2004). The ins and outs of presenilin 1 membrane topology. Proc. Natl. Acad. Sci. U S A101, 905-906. doi: 10.1073/pnas.0307297101
76. Kim, W. Y., and Shen, J. (2008). Presenilins are required for maintenance of neural stem cells in the developing brain. Mol. Neurodegener. 3:2. doi: 10.1186/1750-1326-3-2
77. 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. doi: 10.1074/jbc.m509070200
78. Kimberly, W. T., LaVoie, M. J., Ostaszewski, B. L., Ye, W., Wolfe, M. S., and Selkoe, D. J. (2003). Gamma-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. doi: 10.1073/pnas.1037392100
79. Kinoshita, A., Whelan, C. M., Berezovska, O., and Hyman, B. T. (2002). The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells. J. Biol. Chem. 277, 28530-28536. doi: 10.1074/jbc.m203372200
80. Kopan, R., and Ilagan, M. X. (2004). Gamma-secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, 499-504. doi: 10.1038/nrm1406
81. Kopan, R., and Ilagan, M. X. (2009). The canonical Notch signaling pathway: unfolding the activation mechanism.Cell 137, 216-233. doi: 10.1016/j.cell.2009.03.045
82. Kopan, R., Schroeter, E. H., Weintraub, H., and Nye, J. S. (1996). Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc. Natl. Acad. Sci. U S A93, 1683-1688. doi: 10.1073/pnas.93.4.1683
83. Kumar-Singh, S., Theuns, J., Van Broeck, B., Pirici, D., Vennekens, K., Corsmit, E., et al. (2006). Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum. Mutat. 27, 686-695. doi: 10.1002/humu.20336
84. Lammich, S., Okochi, M., Takeda, M., Kaether, C., Capell, A., Zimmer, A. K., et al. (2002). Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J. Biol. Chem. 277, 44754-44759. doi: 10.1074/jbc.m206872200
85. Laudon, H., Hansson, E. M., Melén, K., Bergman, A., Farmery, M. R., Winblad, B., et al. (2005). A nine-transmembrane domain topology for presenilin 1. J. Biol. Chem. 280, 35352-35360. doi: 10.1074/jbc.m507217200
86. 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. J. Biol. Chem. 278, 37213-37222. doi: 10.1074/jbc.m303941200
87. Lazarov, V. K., Fraering, P. C., Ye, W., Wolfe, M. S., Selkoe, D. J., and Li, H. (2006). 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. doi: 10.1073/pnas.0602321103
88. Lee, S. H., Sharma, M., Südhof, T. C., and Shen, J. (2014). Synaptic function of nicastrin in hippocampal neurons.Proc. Natl. Acad. Sci. U S A 111, 8973-8978. doi: 10.1073/pnas.1408554111
89. Lee, J. H., Yu, W. H., Kumar, A., Lee, S., Mohan, P. S., Peterhoff, C. M., et al. (2010). Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146-1158. doi: 10.1016/j.cell.2010.05.008
90. Leem, J. Y., Vijayan, S., Han, P., Cai, D., Machura, M., Lopes, K. O., et al. (2002). Presenilin 1 is required for maturation and cell surface accumulation of nicastrin. J. Biol. Chem. 277, 19236-19240. doi: 10.1074/jbc.c200148200
91. Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., et al. (1995a). Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973-977. doi: 10.1126/science.7638622
92. Levy-Lahad, E., Wijsman, E. M., Nemens, E., Anderson, L., Goddard, K. A., Weber, J. L., et al. (1995b). A familial Alzheimer's disease locus on chromosome 1. Science 269, 970-973. doi: 10.1126/science.7638621
93. Li, X., Dang, S., Yan, C., Gong, X., Wang, J., and Shi, Y. (2013). Structure of a presenilin family intramembrane aspartate protease. Nature 493, 56-61. doi: 10.1038/nature11801
94. Li, J., Fici, G. J., Mao, C. A., Myers, R. L., Shuang, R., Donoho, G. P., et al. (2003a). Positive and negative regulation of the gamma-secretase activity by nicastrin in a murine model. J. Biol. Chem. 278, 33445-33449. doi: 10.1074/jbc.m301288200
95. Li, Y. M., Lai, M. T., Xu, M., Huang, Q., Dimuzio-Mower, J., Sardana, M. K., et al. (2000). Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc. Natl. Acad. Sci. U S A 97, 6138-6143. doi: 10.1073/pnas.110126897
96. Li, Y., Lu, S. H., Tsai, C. J., Bohm, C., Qamar, S., Dodd, R. B., et al. (2014). Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes. Structure 22, 125-135. doi: 10.1016/j.str.2013.09.018
97. Li, T., Ma, G., Cai, H., Price, D. L., and Wong, P. C. (2003b). 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.
98. Liu, Q., Zerbinatti, C. V., Zhang, J., Hoe, H. S., Wang, B., Cole, S. L., et al. (2007). Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56, 66-78. doi: 10.1016/j.neuron.2007.08.008
99. Loureiro, R. M., Dumin, J. A., McKee, T. D., Austin, W. F., Fuller, N. O., Hubbs, J. L., et al. (2013). Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models. Alzheimers Res. Ther. 5:19. doi: 10.1186/alzrt173
100. Lu, P., Bai, X. C., Ma, D., Xie, T., Yan, C., Sun, L., et al. (2014). Three-dimensional structure of human gamma-secretase. Nature 512, 166-170. doi: 10.1038/nature13567
101. Luo, W. J., Wang, H., Li, H., Kim, B. S., Shah, S., Lee, H. J., et al. (2003). PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J. Biol. Chem. 278, 7850-7854. doi: 10.1074/jbc.c200648200
102. Ma, G., Li, T., Price, D. L., and Wong, P. C. (2005). APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. J. Neurosci. 25, 192-198. doi: 10.1523/jneurosci.3814-04.2005
103. Marambaud, P., Shioi, J., Serban, G., Georgakopoulos, A., Sarner, S., Nagy, V., et al. (2002). A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions.EMBO J. 21, 1948-1956. doi: 10.1093/emboj/21.8.1948
104. Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., and Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U S A 82, 4245-4249. doi: 10.1073/pnas.82.12.4245
105. McColl, G., Roberts, B. R., Pukala, T. L., Kenche, V. B., Roberts, C. M., Link, C. D., et al. (2012). Utility of an improved model of amyloid-beta (Abeta(1)(-)(4)(2)) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease. Mol. Neurodegener. 7:57. doi: 10.1186/1750-1326-7-57
106. Mitani, Y., Yarimizu, J., Saita, K., Uchino, H., Akashiba, H., Shitaka, Y., et al. (2012). Differential effects between gamma-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J. Neurosci. 32, 2037-2050. doi: 10.1523/jneurosci.4264-11.2012
107. Ni, C. Y., Murphy, M. P., Golde, T. E., and Carpenter, G. (2001). gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179-2181. doi: 10.1126/science.1065412
108. Oehlrich, D., Berthelot, D. J., and Gijsen, H. J. (2011). gamma-Secretase modulators as potential disease modifying anti-Alzheimer's drugs. J. Med. Chem. 54, 669-698. doi: 10.1021/jm101168r
109. Ogura, T., Mio, K., Hayashi, I., Miyashita, H., Fukuda, R., Kopan, R., et al. (2006). Three-dimensional structure of the gamma-secretase complex. Biochem. Biophys. Res. Commun. 343, 525-534. doi: 10.1016/j.bbrc.2006.02.158
110. Oh, Y. S., and Turner, R. J. (2005). Topology of the C-terminal fragment of human presenilin 1. Biochemistry 44, 11821-11828. doi: 10.1021/bi0509494
111. Ohki, Y., Shimada, N., Tominaga, A., Osawa, S., Higo, T., Yokoshima, S., et al. (2014). Binding of longer Abeta to transmembrane domain 1 of presenilin 1 impacts on Abeta42 generation. Mol. Neurodegener. 9:7. doi: 10.1186/1750-1326-9-7
112. Okochi, M., Tagami, S., Yanagida, K., Takami, M., Kodama, T. S., Mori, K., et al. (2013). gamma-secretase modulators and presenilin 1 mutants act differently on presenilin/gamma-secretase function to cleave Abeta42 and Abeta43. Cell Rep. 3, 42-51. doi: 10.1016/j.celrep.2012.11.028
113. Olsson, B., Legros, L., Guilhot, F., Strömberg, K., Smith, J., Livesey, F. J., et al. (2014). Imatinib treatment and Abeta42 in humans. Alzheimers Dement. 10, S374-S380. doi: 10.3410/f.12445.469930
114. Osenkowski, P., Li, H., Ye, W., Li, D., Aeschbach, L., Fraering, P. C., et al. (2009). Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J. Mol. Biol. 385, 642-652. doi: 10.1016/j.jmb.2008.10.078
115. Page, R. M., Baumann, K., Tomioka, M., Pérez-Revuelta, B. I., Fukumori, A., Jacobsen, H., et al. (2008). Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J. Biol. Chem. 283, 677-683. doi: 10.1074/jbc.m708754200
116. Pardossi-Piquard, R., Böhm, C., Chen, F., Kanemoto, S., Checler, F., Schmitt-Ulms, G., et al. (2009a). TMP21 transmembrane domain regulates gamma-secretase cleavage. J. Biol. Chem. 284, 28634-28641. doi: 10.1074/jbc.m109.059345
117. Pardossi-Piquard, R., Dunys, J., Giaime, E., Guillot-Sestier, M. V., St George-Hyslop, P., Checler, F., et al. (2009b). p53-dependent control of cell death by nicastrin: lack of requirement for presenilin-dependent gamma-secretase complex. J. Neurochem. 109, 225-237. doi: 10.1111/j.1471-4159.2009.05952.x
118. Pardossi-Piquard, R., Petit, A., Kawarai, T., Sunyach, C., Alves da Costa, C., Vincent, B., et al. (2005). Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP. Neuron 46, 541-554. doi: 10.1016/j.neuron.2005.04.008
119. Pardossi-Piquard, R., Yang, S. P., Kanemoto, S., Gu, Y., Chen, F., Böhm, C., et al. (2009c). APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes. J. Biol. Chem. 284, 16298-16307. doi: 10.1074/jbc.m109.000067
120. Pettersson, M., Kauffman, G. W., am Ende, C. W., Patel, N. C., Stiff, C., Tran, T. P., et al. (2011). Novel gamma-secretase modulators: a review of patents from 2008 to 2010. Expert Opin. Ther. Pat. 21, 205-226. doi: 10.1517/13543776.2011.547479
121. Pettersson, M., Stepan, A. F., Kauffman, G. W., and Johnson, D. S. (2013). Novel gamma-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012. Expert Opin. Ther. Pat. 23, 1349-1366. doi: 10.1517/13543776.2013.821465
122. Podlisny, M. B., Citron, M., Amarante, P., Sherrington, R., Xia, W., Zhang, J., 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. doi: 10.1006/nbdi.1997.0129
123. Portelius, E., Van Broeck, B., Andreasson, U., Gustavsson, M. K., Mercken, M., Zetterberg, H., et al. (2010). Acute effect on the Abeta isoform pattern in CSF in response to gamma-secretase modulator and inhibitor treatment in dogs. J. Alzheimers Dis. 21, 1005-1012. doi: 10.3233/JAD-2010-100573
124. Pratt, K. G., Zimmerman, E. C., Cook, D. G., and Sullivan, J. M. (2011). Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling. Nat. Neurosci. 14, 1112-1114. doi: 10.1038/nn.2893
125. Proctor, C. J., Pienaar, I. S., Elson, J. L., and Kirkwood, T. B. (2012). Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer's disease: a stochastic modelling approach. Mol. Neurodegener. 7:32. doi: 10.1186/1750-1326-7-32
126. Prokop, S., Haass, C., and Steiner, H. (2005). Length and overall sequence of the PEN-2 C-terminal domain determines its function in the stabilization of presenilin fragments. J. Neurochem. 94, 57-62. doi: 10.1111/j.1471-4159.2005.03165.x
127. Prokop, S., Shirotani, K., Edbauer, D., Haass, C., and Steiner, H. (2004). Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex. J. Biol. Chem. 279, 23255-23261. doi: 10.1074/jbc.m401789200
128. Qyang, Y., Chambers, S. M., Wang, P., Xia, X., Chen, X., Goodell, M. A., et al. (2004). Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage. Biochemistry 43, 5352-5359. doi: 10.1021/bi049826u
129. 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. doi: 10.1074/jbc.272.39.24536
130. Renzi, F., Zhang, X., Rice, W. J., Torres-Arancivia, C., Gomez-Llorente, Y., Diaz, R., et al. (2011). Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy. J. Biol. Chem. 286, 21440-21449. doi: 10.1074/jbc.m110.193326
131. 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. doi: 10.1038/376775a0
132. Rogers, K., Felsenstein, K. M., Hrdlicka, L., Tu, Z., Albayya, F., Lee, W., et al. (2012). Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol. Neurodegener. 7:61. doi: 10.1186/1750-1326-7-61
133. Rosén, C., Hansson, O., Blennow, K., and Zetterberg, H. (2013). Fluid biomarkers in Alzheimer's disease - current concepts. Mol. Neurodegener. 8:20. doi: 10.1186/1750-1326-8-20
134. Sastre, M., Steiner, H., Fuchs, K., Capell, A., Multhaup, G., Condron, M. M., et al. (2001). Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch.EMBO Rep. 2, 835-841. doi: 10.1093/embo-reports/kve180
135. Schedin-Weiss, S., Winblad, B., and Tjernberg, L. O. (2014). The role of protein glycosylation in Alzheimer disease.FEBS J. 281, 46-62. doi: 10.1111/febs.12590
136. Schellenberg, G. D., Bird, T. D., Wijsman, E. M., Orr, H. T., Anderson, L., Nemens, E., et al. (1992). Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258, 668-671. doi: 10.1126/science.1411576
137. 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 in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864-870. doi: 10.1038/nm0896-864
138. Schor, N. F. (2011). What the halted phase III gamma-secretase inhibitor trial may (or may not) be telling us. Ann. Neurol. 69, 237-239. doi: 10.1002/ana.22365
139. 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. doi: 10.1038/30756
140. 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. J. Biol. Chem. 278, 46107-46116. doi: 10.1074/jbc.m307757200
141. Seeger, M., Nordstedt, C., Petanceska, S., Kovacs, D. M., Gouras, G. K., Hahne, S., et al. (1997). Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc. Natl. Acad. Sci. U S A 94, 5090-5094. doi: 10.1073/pnas.94.10.5090
142. Selkoe, D. J. (1998). The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease.Trends Cell Biol. 8, 447-453. doi: 10.1016/S0962-8924(98)01363-4
143. Selkoe, D. J. (2001). Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J. Alzheimers Dis. 3, 75-80.
144. Serneels, L., Dejaegere, T., Craessaerts, K., Horré, K., Jorissen, E., Tousseyn, T., et al. (2005). Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc. Natl. Acad. Sci. U S A 102, 1719-1724. doi: 10.1073/pnas.0408901102
145. 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. doi: 10.1016/j.cell.2005.05.022
146. 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. doi: 10.1038/375754a0
147. Shirotani, K., Edbauer, D., Kostka, M., Steiner, H., and Haass, C. (2004). Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1. J. Neurochem. 89, 1520-1527. doi: 10.1111/j.1471-4159.2004.02447.x
148. Siman, R., Reaume, A. G., Savage, M. J., Trusko, S., Lin, Y. G., Scott, R. W., et al. (2000). Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition and neuronal vulnerability. J. Neurosci.20, 8717-8726.
149. Sisodia, S. S., Kim, S. H., and Thinakaran, G. (1999). Function and dysfunction of the presenilins. Am. J. Hum. Genet.65, 7-12. doi: 10.1086/302475
150. Slowik, A., Merres, J., Elfgen, A., Jansen, S., Mohr, F., Wruck, C. J., et al. (2012). Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE)-and amyloid beta 1-42-induced signal transduction in glial cells. Mol. Neurodegener. 7:55. doi: 10.1186/1750-1326-7-55
151. Sobhanifar, S., Schneider, B., Löhr, F., Gottstein, D., Ikeya, T., Mlynarczyk, K., et al. (2010). Structural investigation of the C-terminal catalytic fragment of presenilin 1. Proc. Natl. Acad. Sci. U S A 107, 9644-9649. doi: 10.1073/pnas.1000778107
152. Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., et al. (2002). PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J. Biol. Chem. 277, 39062-39065. doi: 10.1074/jbc.C200469200
153. St George-Hyslop, P., and Fraser, P. E. (2012). Assembly of the presenilin gamma-/epsilon-secretase complex. J. Neurochem. 120(Suppl. 1), 84-88. doi: 10.1111/j.1471-4159.2011.07505.x
154. Swiatek, P. J., Lindsell, C. E., del Amo, F. F., Weinmaster, G., and Gridley, T. (1994). Notch1 is essential for postimplantation development in mice. Genes Dev. 8, 707-719. doi: 10.1101/gad.8.6.707
155. Tabuchi, K., Chen, G., Südhof, T. C., and Shen, J. (2009). Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration. J. Neurosci. 29, 7290-7301. doi: 10.1523/jneurosci.1320-09.2009
156. Takagi, S., Tominaga, A., Sato, C., Tomita, T., and Iwatsubo, T. (2010). Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the gamma-secretase. J. Neurosci. 30, 15943-15950. doi: 10.1523/jneurosci.3318-10.2010
157. Takami, M., Nagashima, Y., Sano, Y., Ishihara, S., Morishima-Kawashima, M., Funamoto, S., et al. (2009). gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J. Neurosci. 29, 13042-13052. doi: 10.1523/jneurosci.2362-09.2009
158. Tamayev, R., and D'Adamio, L. (2012). Inhibition of gamma-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol. Neurodegener. 7:19. doi: 10.1186/1750-1326-7-19
159. 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 in vivo. Neuron 17, 181-190. doi: 10.1016/s0896-6273(00)80291-3
160. Thinakaran, G., Harris, C. L., Ratovitski, T., Davenport, F., Slunt, H. H., Price, D. L., et al. (1997). Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272, 28415-28422. doi: 10.1074/jbc.272.45.28415
161. Thinakaran, G., and Parent, A. T. (2004). Identification of the role of presenilins beyond Alzheimer's disease.Pharmacol. Res. 50, 411-418. doi: 10.1016/j.phrs.2003.12.026
162. Torres, M., Jimenez, S., Sanchez-Varo, R., Navarro, V., Trujillo-Estrada, L., Sanchez-Mejias, E., et al. (2012). Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus. Mol. Neurodegener. 7:59. doi: 10.1186/1750-1326-7-59
163. Tournoy, J., Bossuyt, X., Snellinx, A., Regent, M., Garmyn, M., Serneels, L., et al. (2004). Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. Hum. Mol. Genet. 13, 1321-1331. doi: 10.1093/hmg/ddh151
164. Tu, H., Nelson, O., Bezprozvanny, A., Wang, Z., Lee, S. F., Hao, Y. H., et al. (2006). Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126, 981-993. doi: 10.1016/j.cell.2006.06.059
165. van Es, J. H., van Gijn, M. E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., et al. (2005). Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959-963. doi: 10.1038/nature03659
166. Veeraraghavalu, K., Choi, S. H., Zhang, X., and Sisodia, S. S. (2013). Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors. Mol. Neurodegener.8:41. doi: 10.1186/1750-1326-8-41
167. Vetrivel, K. S., Gong, P., Bowen, J. W., Cheng, H., Chen, Y., Carter, M., et al. (2007). Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism. Mol. Neurodegener. 2:4. doi: 10.1186/1750-1326-2-4
168. Vetrivel, K. S., Zhang, X., Meckler, X., Cheng, H., Lee, S., Gong, P., et al. (2008). Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta. J. Biol. Chem. 283, 19489-19498. doi: 10.1074/jbc.m801037200
169. Vetrivel, K. S., Zhang, Y. W., Xu, H., and Thinakaran, G. (2006). Pathological and physiological functions of presenilins. Mol. Neurodegener. 1:4. doi: 10.1186/1750-1326-1-4
170. von Rotz, R. C., Kohli, B. M., Bosset, J., Meier, M., Suzuki, T., Nitsch, R. M., et al. (2004). The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J. Cell. Sci. 117, 4435-4448. doi: 10.1242/jcs.01323
171. Wang, X., Huang, T., Bu, G., and Xu, H. (2014). Dysregulation of protein trafficking in neurodegeneration. Mol. Neurodegener. 9:31. doi: 10.1186/1750-1326-9-31
172. Wang, H., Luo, W. J., Zhang, Y. W., Li, Y. M., Thinakaran, G., Greengard, P., et al. (2004). Presenilins and gamma-secretase inhibitors affect intracellular trafficking and cell surface localization of the gamma-secretase complex components. J. Biol. Chem. 279, 40560-40566. doi: 10.1074/jbc.m404345200
173. Wang, R., Tang, P., Wang, P., Boissy, R. E., and Zheng, H. (2006). Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer's disease mutation. Proc. Natl. Acad. Sci. U S A 103, 353-358. doi: 10.1073/pnas.0509822102
174. 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. doi: 10.1074/jbc.m509066200
175. 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. doi: 10.1038/35102591
176. Weidemann, A., Eggert, S., Reinhard, F. B., Vogel, M., Paliga, K., Baier, G., et al. (2002). A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing. Biochemistry 41, 2825-2835. doi: 10.1021/bi015794o
177. Wilcock, G. K., Black, S. E., Hendrix, S. B., Zavitz, K. H., Swabb, E. A., Laughlin, M. A., et al. (2008). Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol. 7, 483-493. doi: 10.1016/s1474-4422(08)70090-5
178. Wolfe, M. S., and Selkoe, D. J. (2014). gamma-Secretase: a horseshoe structure brings good luck. Cell 158, 247-249. doi: 10.1016/j.cell.2014.06.043
179. Wolfe, M. S., Xia, W., Ostaszewski, B. L., Diehl, T. S., Kimberly, W. T., and Selkoe, D. J. (1999). Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398, 513-517. doi: 10.1038/19077
180. 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. J. Biol. Chem. 279, 12876-12882. doi: 10.1074/jbc.m311652200
181. Wunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., Neumann, H., and Walter, J. (2013). Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J. Biol. Chem. 288, 33027-33036. doi: 10.1074/jbc.m113.517540
182. Xia, X., Qian, S., Soriano, S., Wu, Y., Fletcher, A. M., Wang, X. J., et al. (2001). Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc. Natl. Acad. Sci. U S A 98, 10863-10868. doi: 10.1073/pnas.191284198
183. Xie, T., Yan, C., Zhou, R., Zhao, Y., Sun, L., Yang, G., et al. (2014). Crystal structure of the gamma-secretase component nicastrin. Proc. Natl. Acad. Sci. U S A 111, 13349-13354. doi: 10.2210/pdb4r12/pdb
184. Yang, D. S., Tandon, A., Chen, F., Yu, G., Yu, H., Arawaka, S., et al. (2002). Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins. J. Biol. Chem. 277, 28135-28142. doi: 10.1074/jbc.m110871200
185. Youmans, K. L., Tai, L. M., Kanekiyo, T., Stine, W. B. Jr., Michon, S. C., Nwabuisi-Heath, E., et al. (2012). Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody. Mol. Neurodegener. 7:8. doi: 10.1186/1750-1326-7-8
186. Yu, G., Chen, F., Levesque, G., Nishimura, M., Zhang, D. M., Levesque, L., 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. doi: 10.1074/jbc.273.26.16470
187. 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. doi: 10.1038/35024009
188. Zhang, Y. W., Luo, W. J., Wang, H., Lin, P., Vetrivel, K. S., Liao, F., et al. (2005). Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components. J. Biol. Chem. 280, 17020-17026. doi: 10.1074/jbc.m409467200
189. Zhang, H., Sun, S., Herreman, A., De Strooper, B., and Bezprozvanny, I. (2010). Role of presenilins in neuronal calcium homeostasis. J. Neurosci. 30, 8566-8580. doi: 10.1523/JNEUROSCI.1554-10.2010
190. Zhang, Y. W., Thompson, R., Zhang, H., and Xu, H. (2011). APP processing in Alzheimer's disease. Mol. Brain. 4:3. doi: 10.1186/1756-6606-4-3
191. Zhang, Y. W., Wang, R., Liu, Q., Zhang, H., Liao, F. F., and Xu, H. (2007). Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc. Natl. Acad. Sci. U S A 104, 10613-10618. doi: 10.1073/pnas.0703903104
192. Zhang, C., Wu, B., Beglopoulos, V., Wines-Samuelson, M., Zhang, D., Dragatsis, I., et al. (2009). Presenilins are essential for regulating neurotransmitter release. Nature 460, 632-636. doi: 10.1038/nature08177
193. Zhao, G., Mao, G., Tan, J., Dong, Y., Cui, M. Z., Kim, S. H., et al. (2004). Identification of a new presenilin-dependent zeta-cleavage site within the transmembrane domain of amyloid precursor protein. J. Biol. Chem. 279, 50647-50650. doi: 10.1074/jbc.c400473200
194. Zhao, G., Tan, J., Mao, G., Cui, M. Z., and Xu, X. (2007). The same gamma-secretase accounts for the multiple intramembrane cleavages of APP. J. Neurochem. 100, 1234-1246. doi: 10.1111/j.1471-4159.2006.04302.x
195. 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. U S A 102, 7499-7504. doi: 10.1073/pnas.0502768102