BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: Implications for Alzheimer’s disease therapeutics
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, beta-amyloid peptides (Abetas), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma-secretases. beta-secretase activity cleaves APP to define the N-terminus of the Abeta1-x peptides and, therefore, has been a long- sought therapeutic target for treatment of AD. The gene encoding a beta-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary beta-secretase in mammalian brain nor whether inhibition of beta-secretase might have effects in mammals that would preclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, beta-secretase activity and Abeta production. These mice appeared to develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable beta-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Abeta from APP. The findings that BACE is the primary beta-secretase activity in brain and that loss of beta-secretase activity produces no profound phenotypic defects with a concomitant reduction in beta-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.
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Many BACE1 knockout mouse phenotypes, such as peripheral hypomyelination and synaptic deficits, result from loss of function of substrates that depend on BACE1 activation.
“Many of the BACE1 KO mouse phenotypes, such as the peripheral hypomyelination and synaptic deficits, are due to loss of function of substrates depending on the activation by BACE1.”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [64]
Cites
Glenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404 · see citing works
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876 · cited 2× · see citing works
“BACE mRNA is expressed widely at low levels, at moderate levels in the brain and at higher levels in the pancreas (9, 11 ).”
BackgroundScheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599 · see citing works
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K., & Van Leuven, F. (1998) · Nature · doi:10.1038/34910 · Cited by 1,818 · see citing works
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J. (1992) · Nature · doi:10.1038/360672a0 · Cited by 1,757 · see citing works
Purification and cloning of amyloid precursor protein β-secretase from human brain
Sinha, S., Anderson, J. P., Barbour, R., Basi, G. S., Caccavello, R., Davis, D., Doan, M., Dovey, H. F., Frigon, N., Hong, J., et al. (1999) · Nature · doi:10.1038/990114 · Cited by 1,612 · see citing works
Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., Prada, C.-M., Kim, G., Seekins, S., Yager, D., et al. (1996) · Neuron · doi:10.1016/s0896-6273(00)80230-5 · Cited by 1,478 · see citing works
Suzuki, N., Cheung, T. T., Cai, X.-D., Odaka, A., Otvos, L., Eckman, C., Golde, T. E., & Younkin, S. G. (1994) · Science · doi:10.1126/science.8191290 · Cited by 1,471 · see citing works
Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity
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., Buhl, A. E., et al. (1999) · Nature · doi:10.1038/990107 · Cited by 1,438 · see citing works
Correlation Between Elevated Levels of Amyloid β-Peptide in the Brain and Cognitive Decline
Näslund, J. (2000) · JAMA · doi:10.1001/jama.283.12.1571 · Cited by 1,268 · see citing works
Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase
Hussain, I., Powell, D., Howlett, D. R., Tew, D. G., Meek, T. D., Chapman, C., Gloger, I. S., Murphy, K. E., Southan, C. D., Ryan, D. M., et al. (1999) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.1999.0811 · Cited by 1,080 · see citing works
Luo, Y., Bolon, B., Kahn, S., Bennett, B. D., Babu-Khan, S., Denis, P., Fan, W., Kha, H., Zhang, J., Gong, Y., et al. (2001) · Nature Neuroscience · doi:10.1038/85059 · Cited by 1,001 · see citing works
Neurotoxicity of a Fragment of the Amyloid Precursor Associated with Alzheimer's Disease
Yankner, B. A., Dawes, L. R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M. L., & Neve, R. L. (1989) · Science · doi:10.1126/science.2474201 · Cited by 907 · see citing works
Normal and Abnormal Biology of the Beta-Amyloid Precursor Protein
Selkoe, D. J. (1994) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.17.030194.002421 · Cited by 827 · see citing works
Skeletal and CNS Defects in Presenilin-1-Deficient Mice
Shen, J., Bronson, R. T., Chen, D. F., Xia, W., Selkoe, D. J., & Tonegawa, S. (1997) · Cell · doi:10.1016/s0092-8674(00)80244-5 · Cited by 808 · see citing works
Rogers, D. C., Fisher, E. M. C., Brown, S. D. M., Peters, J., Hunter, A. J., & Martin, J. E. (1997) · Mammalian Genome · doi:10.1007/s003359900551 · Cited by 795 · see citing works
BACE1 is the major β-secretase for generation of Aβ peptides by neurons
Cai, H., Wang, Y.-S., McCarthy, D., Wen, H., Borchelt, D., Price, D. L., & Wong, P. (2001) · Nature Neuroscience · doi:10.1038/85064 · Cited by 791 · see citing works
Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein
Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A., & Tang, J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1456 · Cited by 769 · see citing works
Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm
Wong, P. C., Zheng, H., Chen, H., Bêcher, M. W., SIRINATHSINGHJI, D. J. S., Trumbauer, M. E., Chen, H. Y., Price, D. L., der Ploeg, L. H. T. V., & Sisodia, S. S. (1997) · Nature · doi:10.1038/387288a0 · Cited by 712 · see citing works
Johnson‐Wood, K., Lee, M., Motter, R. N., Hu, K., Gordon, G., Barbour, R., Khan, K., Gordon, M. N., Tan, H. T., Games, D., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.4.1550 · Cited by 634 · see citing works
Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide
Seubert, P. A., Oltersdorf, T., Lee, M., Barbour, R., Blomquist, C. L., Davis, D. L., Bryant, K., Fritz, L. C., Galasko, D., Thal, L. J., et al. (1993) · Nature · doi:10.1038/361260a0 · Cited by 552 · see citing works
Presenilin-1 and -2 Are Molecular Targets for γ-Secretase Inhibitors
Seiffert, D., Bradley, J. D., Rominger, C. M., Rominger, D. H., Yang, F., Meredith, J. E., Wang, Q., Roach, A., Thompson, L. A., Spitz, S. M., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005430200 · Cited by 301 · see citing works
Construction of Gene Targeting Vectors from λKOS Genomic Libraries
Wattler, S., Kelly, M. D., & Nehls, M. C. (1999) · BioTechniques · doi:10.2144/99266rr02 · Cited by 99 · see citing works
Bodendorf, U., Fischer, F., Bodian, D. L., Multhaup, G., & Paganetti, P. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008861200 · Cited by 77 · see citing works
Handyside, A. H., O'Neill, G. T., Jones, M., et al. (1989) · Development Genes and Evolution · doi:10.1007/bf00376370 · Cited by 76 · see citing works
Normal and Abnormal Biology of the Beta-Amyloid Precursor Protein
Dj, S. (1994) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.17.1.489 · Cited by 25 · see citing works
Two automated locomotor activity tests for dopamine autoreceptor agonists
Schreur, P. J. K. D., & Nichols, N. F. (1986) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(86)90263-7 · Cited by 5 · see citing works
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Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052 · see citing works
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Haass, C., Kaether, C., Thinakaran, G., & Sisodia, S. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006270 · Cited by 1,075 · see citing works
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Willem, M., Garratt, A. N., Novak, B., Citron, M., Kaufmann, S., Rittger, A., DeStrooper, B., Saftig, P., Birchmeier, C., & Haass, C. (2006) · Science · doi:10.1126/science.1132341 · Cited by 703 · see citing works
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Hu, X., Hicks, C. W., He, W., Wong, P., Macklin, W. B., Trapp, B. D., & Yan, R. (2006) · Nature Neuroscience · doi:10.1038/nn1797 · Cited by 608 · see citing works
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Ly, P. T. T., Wu, Y., Zou, H., Wang, R., Zhou, W., Kinoshita, A., Zhang, M., Yang, Y., Cai, F., Woodgett, J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64516 · Cited by 442 · see citing works
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- Authors
- Roberds, S. L.
- Corresponding author
- Roberds, S. L.
- ORCID
- Roberds, S. L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-06-01
- Volume
- 10
- Issue
- 12
- Pages
- 1317-1324
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2155237226
- Cited by
- 705
- References
- 27
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 9 · 2023: 8 · 2022: 11 · 2021: 11 · 2020: 15 · 2019: 29 · 2018: 24 · 2017: 27 · 2016: 29 · 2015: 20 · 2014: 40 · 2013: 37 · 2012: 41
- FWCI
- 22.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- beta-secretase, Alzheimer's disease, amyloid-beta, amyloid precursor protein, beta-secretase inhibition, therapeutic target, amyloid plaques, cortical cultures
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Line, Cells, Cultured, Enzyme Inhibitors, Female, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Endopeptidases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Knockout, Culture Techniques, Mice, Amyloid Precursor Protein Secretases
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