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A γ‐secretase inhibitor decreases amyloid‐β production in the central nervous system
Open accessAbstract
Objective: Accumulation of amyloid‐β (Aβ) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Aβ production or clearance in the human CNS. The objective of this study was to determine the effects of a γ‐secretase inhibitor on the production of Aβ in the human CNS. Methods: We utilized a recently developed method of stable‐isotope labeling combined with cerebrospinal fluid sampling to directly measure Aβ production during treatment of a γ‐secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Aβ production in healthy men (age range, 21–50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group). Results: LY450139 significantly decreased the production of CNS Aβ in a dose‐dependent fashion, with inhibition of Aβ generation of 47, 52, and 84% over a 12‐hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Aβ clearance. Interpretation: Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease‐modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009
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“evidence for this possibility comes from animal models in which exogenously applied or genetically overexpressed Aβ production diminished vasodilation to pharmacological or physiological stimuli, even in the absence of vascular Aβ deposits.115,160,161”
From Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association (2011) · cites this paper as [160]
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Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744
Blennow, K., de Leon, M. J., & Zetterberg, H. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69113-7 · Cited by 3,134
Alzheimer Disease in the US Population: Prevalence Estimates Using the 2000 Census
Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A., & Evans, D. A. (2003) · Archives of Neurology · doi:10.1001/archneur.60.8.1119 · Cited by 2,168
Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease
Walsh, D. M., & Selkoe, D. J. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.010 · Cited by 1,207
Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain
Dovey, H. F., John, V., Anderson, J. P., Chen, L. Z., Andrieu, P. D. S. I., Fang, L. Y., Freedman, S. B., Folmer, B., Goldbach, E. G., Holsztynska, E. J., et al. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00012.x · Cited by 870
Self-citationThe discovery and development of HMG-CoA reductase inhibitors.
Endo, A. (1992) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)41379-3 · Cited by 847
Wong, G. T., Manfra, D. J., Poulet, F. M., Zhang, Q., Josien, H. B., Bara, T. A., Engstrom, L., Pinzon-Ortiz, M. C., Fine, J. S., Lee, H.-J. J., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311652200 · Cited by 723
Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo
Bateman, R. J., Munsell, L. Y., Morris, J. C., Swarm, R., Yarasheski, K. E., & Holtzman, D. M. (2006) · Nature Medicine · doi:10.1038/nm1438 · Cited by 599
Self-citationNEURODEGENERATIVE DISEASES: New Concepts of Pathogenesis and Their Therapeutic Implications
Skovronsky, D., Lee, V. M. ‐., & Trojanowski, J. Q. (2006) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.1.110304.100113 · Cited by 433
Cirrito, J. R., May, P. C., O'Dell, M. A., Taylor, J. W., Parsadanian, M., Cramer, J. W., Audia, J. E., Nissen, J. S., Bales, K. R., Paul, S. M., et al. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-26-08844.2003 · Cited by 394
Self-citationEffects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease
Siemers, E., Quinn, J. F., Kaye, J. A., Farlow, M. R., Porsteinsson, A. P., Tariot, P. N., Zoulnouni, P., Galvin, J. E., Holtzman, D. M., Knopman, D. S., et al. (2006) · Neurology · doi:10.1212/01.wnl.0000198762.41312.e1 · Cited by 291
Self-citationMabuchi, H., Haba, T., Tatami, R., Miyamoto, S., Sakai, Y., Wakasugi, T., Watanabe, A., Koizumi, J., & Takeda, R. (1981) · New England Journal of Medicine · doi:10.1056/nejm198108273050902 · Cited by 262
Fluctuations of CSF amyloid-β levels: Implications for a diagnostic and therapeutic biomarker
Bateman, R. J., Wen, G., Morris, J. C., & Holtzman, D. M. (2007) · Neurology · doi:10.1212/01.wnl.0000256043.50901.e3 · Cited by 260
Self-citationTherapeutic effects of ML-236B in primary hypercholesterolemia
Yamamoto, A., Sudo, H., & Endo, A. (1980) · Atherosclerosis · doi:10.1016/0021-9150(80)90124-0 · Cited by 231
Siemers, E., Skinner, M., Dean, R. A., Gonzales, C., Satterwhite, J. H., Farlow, M. R., NESS, D. K., & May, P. C. (2005) · Clinical Neuropharmacology · doi:10.1097/01.wnf.0000167360.27670.29 · Cited by 215
Self-citationSiemers, E., Dean, R. A., Friedrich, S. W., Ferguson‐Sells, L. R., Gonzales, C., Farlow, M. R., & May, P. C. (2007) · Clinical Neuropharmacology · doi:10.1097/wnf.0b013e31805b7660 · Cited by 154
Self-citationFilling the Gaps in the Aβ Cascade Hypothesis of Alzheimers Disease
Golde, T. E., Dickson, D. W., & Hutton, M. L. (2006) · Current Alzheimer Research · doi:10.2174/156720506779025189 · Cited by 114
Imbimbo, B. P., Giudice, E. D., Colavito, D., D’Arrigo, A., Carbonare, M. D., Villetti, G., Facchinetti, F., Volta, R., Pietrini, V., Baroc, M. F., et al. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.129007 · Cited by 84
Best, J. D., Smith, D. W., Reilly, M., O’Donnell, R., Lewis, H. D., Ellis, S., Wilkie, N., Rosahl, T. W., Laroque, P. A., Boussiquet-Leroux, C., et al. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.114330 · Cited by 84
Moderate Reduction of γ-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities
Li, T., Wen, H., Brayton, C. F., Laird, F. M., Ma, G., Peng, S., Placanica, L., Wu, T. C., Crain, B. J., Price, D. L., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2152-07.2007 · Cited by 80
Bateman, R. J., Munsell, L. Y., Chen, X., Holtzman, D. M., & Yarasheski, K. E. (2007) · Journal of the American Society for Mass Spectrometry · doi:10.1016/j.jasms.2007.02.009 · Cited by 77
Self-citationHyde, L. A., McHugh, N. A., Chen, J., Zhang, Q., Manfra, D. J., Nomeir, A. A., Josien, H. B., Bara, T. A., Clader, J. W., Zhang, L., et al. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.111716 · Cited by 69
Mabuchi, H., Haba, T., TATAMI, R., Miyamoto, S., Sakai, Y., WAKASUGI, T., Watanabe, A., Koizumi, J., & Takeda, R. (2004) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2004.08.023 · Cited by 21
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Karran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188
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Blennow, K., Hampel, H., Weiner, M., & Zetterberg, H. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.4 · Cited by 1,863
Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.56 · Cited by 1,853
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Metadata
- Authors
- Bateman, R. J., Siemers, E. R., Mawuenyega, K. G., Wen, G., Browning, K. R., Sigurdson, W. C., Yarasheski, K. E., Friedrich, S. W., DeMattos, R. B., May, P. C., Paul, S. M., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Bateman, Randall J.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2009-04-09
- Volume
- 66
- Issue
- 1
- Pages
- 48-54
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2730994
- OpenAlex
- W139300322
- Cited by
- 322
- References
- 25
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 4 · 2023: 5 · 2022: 13 · 2021: 13 · 2020: 16 · 2019: 11 · 2018: 7 · 2017: 12 · 2016: 16 · 2015: 19 · 2014: 32 · 2013: 31 · 2012: 39
- FWCI
- 28.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p60dk020579-35, 5p41rr000954-34, UL1TR000448)
- National Institute on Aging (K23AG030946)
- National Institute of Diabetes and Digestive and Kidney Diseases (2P60 DK020579-31, SP30 DK056341-08, P60-DK-020579, P30DK056341, P30DK020579)
- National Center for Research Resources (P41-RR000954, 5P41 RR000954-32, UL1RR024992)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- gamma-secretase inhibitors, amyloid-beta production, amyloid-beta clearance, Alzheimer's disease, central nervous system, stable isotope labeling, cerebrospinal fluid, dose-dependent inhibition
- MeSH terms
- Adult, Alanine, Azepines, Central Nervous System, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme Inhibitors, Humans, Male, Middle Aged, Time Factors, Amyloid beta-Peptides, Area Under Curve, Tandem Mass Spectrometry, Amyloid Precursor Protein Secretases, Young Adult
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