Cited by 328Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

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A γ‐secretase inhibitor decreases amyloid‐β production in the central nervous system

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Bateman, Randall J., Siemers, Eric R., Mawuenyega, Kwasi G., Wen, Guolin, Browning, Karen R., Sigurdson, Wendy C., Yarasheski, Kevin E., Friedrich, Stuart W., DeMattos, Ronald B., May, Patrick C., Paul, Steven M., Holtzman, David M.·2009·Annals of Neurology

DOI 10.1002/ana.21623PMC PMC2730994

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Abstract

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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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: Bateman, Randall J.
Siemers, Eric R.
Yarasheski, Kevin E.
DeMattos, Ronald B.
May, Patrick C.
Paul, Steven M.
Holtzman, David M.
Venue: Annals of Neurology
Publisher: Wiley
Published: 2009-04-09
Volume: 66
Issue: 1
Pages: 48-54
ISSN: 0364-5134 (ISSN-L)
1531-8249
DOI: 10.1002/ana.21623
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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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A γ‐secretase inhibitor decreases amyloid‐β production in the central nervous system

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