NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Open accessAbstract
Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.
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The first gamma-secretase modulators were discovered by recognizing that ibuprofen, indomethacin, and sulindac reduce Aβ42 levels through modulation of gamma-secretase activity.
“The first GSMs were discovered by recognizing that ibuprofen, indomethacin and sulindac reduce Abeta42 levels (Weggen et al., 2001) through modulation of gamma-secretase activity (Eriksen et al., 2003).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Eriksen et al., 2003
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- Authors
- Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., & Golde, T. E.
- Affiliations
- Mayo Clinic (US)
- University of California San Diego (US)
- Corresponding author
- Golde, Todd E.
- Venue
- Journal of Clinical Investigation
- Published
- 2003-08-01
- Volume
- 112
- Issue
- 3
- Pages
- 440-449
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC166298
- OpenAlex
- W2103071556
- Cited by
- 634
- References
- 52
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 11 · 2023: 11 · 2022: 15 · 2021: 20 · 2020: 14 · 2019: 15 · 2018: 11 · 2017: 18 · 2016: 25 · 2015: 18 · 2014: 31 · 2013: 32 · 2012: 37
- FWCI
- 23.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Foundation for Medical Education and Research
- National Institutes of Health
- National Institute on Aging (P01AG020206, T32AG000216)
- National Institute of Neurological Disorders and Stroke (R01NS039072)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- nonsteroidal anti-inflammatory drugs, gamma-secretase, amyloid-beta 42, Alzheimer's disease, APP transgenic mice, ibuprofen, meclofenamic acid, dapsone, cyclooxygenase inhibition, drug repurposing
- MeSH terms
- Alzheimer Disease, Animals, Anti-Inflammatory Agents, Non-Steroidal, Brain, Cell Line, Female, Flurbiprofen, Humans, Meclofenamic Acid, Mice, Transgenic, Peptide Fragments, Endopeptidases, Protease Inhibitors, Stereoisomerism, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Amyloid Precursor Protein Secretases
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