β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's Disease

Frontiers in Aging Neuroscience

Volumn 6, Issue JUN, 2014, Pages 1-20

  Menting, Kelly W ^a   Claassen, Jurgen A H R ^a  

^a RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Alzheimer's disease; Amyloid cascade hypothesis; Amyloid ; APP; BACE1; Drug; secretase; secretase inhibitors

Indexed keywords

5,6 DIHYDRO 2 IMINO 3 METHYL 6 [4 [5 (1 PROPYNYL) 3 PYRIDINYL] 2 THIENYL] 4 PYRIMIDINONE; AMYLOID BETA PROTEIN; ASPARTIC PROTEINASE; BETA SECRETASE INHIBITOR; CTS 21166; LY 2886721; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ARTICLE; CEREBROSPINAL FLUID; DISEASE COURSE; DRUG HALF LIFE; ENZYME ACTIVITY; ENZYME SYNTHESIS; HUMAN; HYPOTHESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN AGGREGATION; PROTEIN STABILITY;

EID: 84904557569     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2014.00165     Document Type: Article

References (60)

1. Bennett, B. D., Babu-Khan, S., Loeloff, R., Louis, J.-C., Curran, E., Citron, M. and Vassar, R. (2000) 'Expression analysis of BACE2 in brain and peripheral tissues', Journal of Biological Chemistry, 275(27), 20647-20651.
2. Berg, J. T., John; Stryer, Lubert (2002) Biochemistry, W. H. Freeman & Co Ltd [online], available: [accessed
3. Bodendorf, U., Fischer, F., Bodian, D., Multhaup, G. and Paganetti, P. (2001) 'A splice variant of β-secretase deficient in the amyloidogenic processing of the amyloid precursor protein', Journal of Biological Chemistry, 276(15), 12019-12023.
4. Bowman Rogers, M. S., Gabrielle (2013) 'BACE inhibitors barrel forward - Next Hurdles: safety, efficacy', [online], available: http://www.alzforum.org/new/detail.asp?id=3441 [accessed 18-06-2014].
5. Britsch (2007) 'The neuregulin-I/ErbB signalling system in development and disease', Advances in anatomy, embryology and cell biology, 190, 65.
6. Cai, H., Wang, Y., McCarthy, D., Wen, H., Borchelt, D. R., Price, D. L. and Wong, P. C. (2001) 'BACE1 is the major β-secretase for generation of Aβ peptides by neurons', Nature neuroscience, 4(3), 233-234.
7. Cheret, C. W., Michael; Fricker, Florence; Wende, Hagen; Wulf-Godlenberg, Annika; Tahirovic, Sabina; Nave, Klaus-Armin; Saftig, Paul; Haass, Christian; Garratt, Alistair; Bennet, David; Birchmeier, Carmen (2013) 'Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles', The EMBO Journal, 14.
8. Citron, M. (2004) 'Beta-secretase inhibition for the treatment of Alzheimer's disease - promise and challenge', TRENDS in pharmacological sciences, 25(2), 5.
9. 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 β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production', Nature, 360(6405), 672-674.
10. Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P. and Davis, A. (1997) 'Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice', Nature medicine, 3(1), 67-72.
11. Cole, S. L. and Vassar, R. (2007) 'The Alzheimer's disease β-secretase enzyme, BACE1', Molecular neurodegeneration, 2(1), 22.
12. Dash, C. K., Aarohi; Dunn, Ben; Rao, Mala (2003) 'Aspartic peptidase inhibitors: Implications in drug development', Critical reviews in biochemistry and molecular biology, 38(2), 30.
13. Dobrowolska, J. A., Michener, M. S., Wu, G., Patterson, B. W., Chott, R., Ovod, V., Pyatkivskyy, Y., Wildsmith, K. R., Kasten, T. and Mathers, P. (2014) 'CNS Amyloid- β, Soluble APP-a and-β Kinetics during BACE Inhibition', The Journal of neuroscience, 34(24), 8336-8346.
14. Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D., Ozols, V. V., Jessing, K. W., Zavitz, K. H. and Koo, E. H. (2003) 'NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo', Journal of Clinical Investigation, 112(3), 440-449.
15. Forman, M., Tseng, J., Palcza, J., Leempoels, J., Ramael, S., Krishna, G., Ma, L., Wagner, J. and Troyer, M. (2012) 'The Novel BACE Inhibitor MK-8931 Dramatically Lowers CSF Aβ Peptides in Healthy Subjects: Results from a Rising Single Dose Study (PL02. 004) 64th American Academy of Neu-rology Annual Meeting; 2012', New Orleans: Neurology.
16. Forman MS, P. J., Tseng J, Dockendorf M, Canales C, Apter J, Backonja M, Bryan E, Ereshefsky L, Gevorkyan H, Jhee S, Ostler R, Zari A, Kleijn HJ, laterza O, Ma L, Stone J, Tanen M, Wagner JA, Troyer MD (2013) 'The novel BACe inhibitor MK- 8931 dramatically lowers CSF Abeta peptide in patients with mild to moderate Alzheimer's disease', in The 11th International Conference on Alzheimer's and Parkinson's Disease, Florence, Italy,
17. Fukumoto, H., Cheung, B. S., Hyman, B. T. and Irizarry, M. C. (2002) '{beta}-Secretase protein and activity are increased in the neocortex in Alzheimer disease', Archives of neurology, 59(9), 1381.
18. Ghosh, A. K., Shin, D., Downs, D., Koelsch, G., Lin, X., Ermolieff, J. and Tang, J. (2000) 'Design of potent inhibitors for human brain memapsin 2 (β-secretase)', Journal of the American Chemical Society, 122(14), 3522-3523.
19. Ghosh, A. K. B., Margherita; Tang, Jordan (2012) 'Developing beta-secretase inhibitors for treatment of Alzheimer's disease', Journal of neurochemistry, 120(1), 12.
20. Golde, T. E., Dickson, D. and Hutton, M. (2006) 'Filling the Gaps in the A Cascade Hypothesis of Alzheimers Disease', Current Alzheimer Research, 3(5), 421-430.
21. Green, R. C., Schneider, L. S., Amato, D. A., Beelen, A. P., Wilcock, G., Swabb, E. A., Zavitz, K. H. and Group, T. P. S. (2009) 'Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial', Jama, 302(23), 2557-2564.
22. Hey J. A., K. G., Bilcer G., Jacobs A., Tolar M., Tang J., Ghosh A. K., Hsu H. H. (2008) Single Dose Administration of the b-Secretase Inhibitor CTS21166 (ASP1720) Reduces Plasma Ab40 in Human Subjects, translated by Chicago.
23. Holsinger, R., McLean, C. A., Beyreuther, K., Masters, C. L. and Evin, G. (2002) 'Increased expression of the amyloid precursor β-secretase in Alzheimer's disease', Annals of neurology, 51(6), 783-786.
24. Hong, L., Turner, R. T., Koelsch, G., Shin, D., Ghosh, A. K. and Tang, J. (2002) 'Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3', Biochemistry, 41(36), 10963-10967.
25. Hu, X., Hicks, C. W., He, W., Wong, P., Macklin, W. B., Trapp, B. D. and Yan, R. (2006) 'Bace1 modulates myelination in the central and peripheral nervous system', Nature neuroscience, 9(12), 1520-1525.
26. Hussain, I., Powell, D., Howlett, D. R., Tew, D. G., Meek, T. D., Chapman, C., Gloger, I. S., Murphy, K. E., Southan, C. D. and Ryan, D. M. (1999) 'Identification of a novel aspartic protease (Asp 2) as β-secretase', Molecular and Cellular Neuroscience, 14(6), 419-427.
27. Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D. and Maloney, J. (2012) 'A mutation in APP protects against Alzheimer/'s disease and age-related cognitive decline', Nature, 488(7409), 96-99.
28. Koelsch G. (2008) Beta-Secretase Inhibitor CTS-21166 reduces plasma Abeta-40 in human subjects., translated by Keystone, Colorado: March 24-28.
29. Kuhn, P.-H., Koroniak, K., Hogl, S., Colombo, A., Zeitschel, U., Willem, M., Volbracht, C., Schepers, U., Imhof, A. and Hoffmeister, A. (2012) 'Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons', The EMBO Journal, 31(14), 3157-3168.
30. Kuo, Y.-M., Emmerling, M. R., Vigo-Pelfrey, C., Kasunic, T. C., Kirkpatrick, J. B., Murdoch, G. H., Ball, M. J. and Roher, A. E. (1996) 'Water-soluble A (N-40, N-42) oligomers in normal and Alzheimer disease brains', Journal of Biological Chemistry, 271(8), 4077-4081.
31. Lai R, A. b., Kaplow JM, et al. (2013) 'Novel BACE1 i nhibitor E2609 reduces plasma and CSF amyloid in healthy subjects after 14 days oral administration', in The 11th International Conference on Alzheimer's and Parkinson's Diseases, Florance, Italy, March 6-10, 2013
32. Lai, R., Albala, B., Kaplow, J. M., Aluri, J., Yen, M. and Satlin, A. (2012) 'First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing', Alzheimer's & Dementia, 8(4), P96.
33. Laird, F. M., Cai, H., Savonenko, A. V., Farah, M. H., He, K., Melnikova, T., Wen, H., Chiang, H.-C., Xu, G. and Koliatsos, V. E. (2005) 'BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions', The Journal of neuroscience, 25(50), 11693-11709.
34. Landhuis, E. (2012) 'Wave of New BACE inhibitors heading to phase 2', [online], available: www.alzforum.org/new/detail.asp?id=3222 [accessed
35. Lemere, C., Blusztajn, J., Yamaguchi, H., Wisniewski, T., Saido, T. and Selkoe, D. (1996) 'Sequence of deposition of heterogeneous amyloid β-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation', Neurobiology of disease, 3(1), 16-32.
36. Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A. and Tang, J. (2000) 'Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein', Proceedings of the National Academy of Sciences, 97(4), 1456-1460.
37. Luo, X. Y., Riqiang (2010) 'Inhibition of BACE1 for therapeutic use in Alzheimer's disease', Int J Clin Exp Pathol, 3(6), 10.
38. Luo, Y., Bolon, B., Kahn, S., Bennett, B. D., Babu-Khan, S., Denis, P., Fan, W., Kha, H., Zhang, J. and Gong, Y. (2001) 'Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation', Nature neuroscience, 4(3), 231-232.
39. Ohno, M., Sametsky, E. A., Younkin, L. H., Oakley, H., Younkin, S. G., Citron, M., Vassar, R. and Disterhoft, J. F. (2004) 'BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease', Neuron, 41(1), 27-33.
40. Rajapaksha, T. W., Eimer, W. A., Bozza, T. C. and Vassar, R. (2011) 'The Alzheimer's beta-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb', Mol. Neurodegener, 6, 88.
41. Roberds, S. L., Anderson, J., Basi, G., Bienkowski, M. J., Branstetter, D. G., Chen, K. S., Freedman, S., Frigon, N. L., Games, D. and Hu, K. (2001) 'BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics', Human molecular genetics, 10(12), 1317-1324.
42. Rogers, M. (2013) 'Lilly Halts Phase 2 Trial of BACE Inhibitor Due to Liver Toxicity', [online], available: http://www.alzforum.org/new/detail.asp?id=3522 [accessed
43. Roßner, S., Sastre, M., Bourne, K. and Lichtenthaler, S. F. (2006) 'Transcriptional and translational regulation of BACE1 expression-implications for Alzheimer's disease', Progress in neurobiology, 79(2), 95-111.
44. Saunders, A. J., Kim, T.-W. and Tanzi, R. E. (1999) 'BACE maps to chromosome 11 and a BACE homolog, BACE2, reside in the obligate Down syndrome region of chromosome 21', Science, 286(5443), 1255-1255.
45. Saxena, S. W., Marc (2012) Dementia, a public health priority, who.int: World Health Organization.
46. Schmechel, D., Saunders, A., Strittmatter, W., Crain, B. J., Hulette, C., Joo, S., Pericak-Vance, M., Goldgaber, D. and Roses, A. (1993) 'Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in lateonset Alzheimer disease', Proceedings of the National Academy of Sciences, 90(20), 9649-9653.
47. Selkoe, D. J. (1991) 'The molecular pathology of Alzheimer's disease', Neuron, 6(4), 487-498.
48. Sinha, S., Anderson, J. P., Barbour, R., Basi, G. S., Caccavello, R., Davis, D., Doan, M., Dovey, H. F., Frigon, N. and Hong, J. (1999) 'Purification and cloning of amyloid precursor protein β-secretase from human brain', Nature, 402(6761), 537-540.
49. Strobel, G. (2008) 'Keystone Drug News: coMentis BACE inhibitor debuts', [online], available: http://www.alzforum.org/new/detail.asp?id=1790 [accessed
50. Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P. and Loeloff, R. (1999) 'β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE', Science, 286(5440), 735-741.
51. Vassar, R. and Kandalepas, P. C. (2011) 'The beta-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease', Alzheimers Res Ther, 3(3), 20.
52. Walker, L. C. and Rosen, R. F. (2006) 'Alzheimer therapeutics-what after the cholinesterase inhibitors?', Age and ageing, 35(4), 332-335.
53. WHO (2012) Dementia, a public health priority, World Health Organization.
54. Willem, M., Garratt, A. N., Novak, B., Citron, M., Kaufmann, S., Rittger, A., DeStrooper, B., Saftig, P., Birchmeier, C. and Haass, C. (2006) 'Control of peripheral nerve myelination by the β-secretase BACE1', Science, 314(5799), 664-666.
55. Willis, B., Martenyi, F., Dean, R., Lowe, S., Nakano, M., Monk, S., Gonzales, C., Mergott, D., Daugherty, L. and Citron, M. (2012) 'Central BACE1 inhibition by LY2886721 produces opposing effects on APP processing as reflected by cerebrospinal fluid sAPPalpha and sAPPbeta', Alzheimer's & Dementia, 8(4), P582.
56. Wilmo, A. P., Martin (2010) World Alzheimer Report 2010, The global economic impact of dementia, Alzheimer's Disease International.
57. 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 ?-secretase activity', Nature, 398(6727), 513-517.
58. Xiulian Sun, G. H., Weihong Song (2006) 'BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome', FASEB J, 20(9), 5.
59. Yan, R., Bienkowski, M. J., Shuck, M. E., Miao, H., Tory, M. C., Pauley, A. M., Brashler, J. R., Stratman, N. C., Mathews, W. R. and Buhl, A. E. (1999) 'Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity', Nature, 402(6761), 533-537.
60. Zhou, L., Barão, S., Laga, M., Bockstael, K., Borgers, M., Gijsen, H., Annaert, W., Moechars, D., Mercken, M. and Gevaer, K. (2012) 'The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo', Journal of Biological Chemistry, 287(31), 25927-25940.