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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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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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