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
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
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Article Neuroscience

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

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.

Authors

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

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IP/MS analysis of Aβ in the media of racemic, R- and S-flurbiprofen–trea...
IP/MS analysis of Aβ in the media of racemic, R- and S-flurbiprofen–treated cells. Plots shown are representative of two experiments, each performed in duplicate. CHO cells overexpressing APP751 and PS1ML were pretreated overnight with ethanol (a), 250 μM racemic flurbiprofen (b), 250 μM S-flurbiprofen (c), or 250 μM R-flurbiprofen (d). Conditioned medium was collected and analyzed after an additional 24 hours of treatment with the same concentration of the drug. Aβ peptides identified by their masses are indicated above the peaks. All forms of flurbiprofen reduce the Aβ42 peak and increase the levels of shorter Aβ derivatives to approximately the same extent. This effect is best seen by comparing the peak heights of the various peptides to the peak height of Aβ1–40, which is largely unchanged.