NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo

Jason L. Eriksen, Sarah A. Sagi, Tawnya E. Smith, Sascha Weggen, Pritam Das, D. C. McLendon, Victor V. Ozols, Kevin W. Jessing, Kenton H. Zavitz, Edward H. Koo, Todd E. Golde

Research output: Contribution to journalArticle

Abstract

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 β protein (Aβ42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid β protein precursor (APP) transgenic mice, and plasma and brain levels of Aβ and the drug were evaluated. These studies show that (a) eight FDA-approved NSAIDs lower Aβ42 in vivo, (b) the ability of an NSAID to lower Aβ42 levels in cell culture is highly predicative of its in vivo activity, (c) in vivo Aβ42 lowering in mice occurs at drug levels achievable in humans, and (d) there is a significant correlation between Aβ42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Aβ42 levels in broken cell γ-secretase assays, indicating that these compounds directly target the γ-secretase complex that generates Aβ from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Aβ42 levels to the greatest extent. Because R-flurbiprofen reduces Aβ42 levels by targeting γ-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Aβ42 lowering agent.

Original languageEnglish (US)
Pages (from-to)440-449
Number of pages10
JournalJournal of Clinical Investigation
Volume112
Issue number3
DOIs
StatePublished - Aug 2003

ASJC Scopus subject areas

  • Medicine(all)

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    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. (2003). NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. Journal of Clinical Investigation, 112(3), 440-449. https://doi.org/10.1172/JCI200318162