NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Jason L. Eriksen, … , Edward H. Koo, Todd E. Golde
Jason L. Eriksen, … , Edward H. Koo, Todd E. Golde
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):440-449. https://doi.org/10.1172/JCI18162.
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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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Effects of NSAIDs on Aβ42 in Tg2576 brain. The graphs illustrate the per...
Effects of NSAIDs on Aβ42 in Tg2576 brain. The graphs illustrate the percent of control values seen in each experimental group ± SEM, and the number in parentheses indicates mice per group. Treated groups were compared with controls using ANOVA with Dunnet’s post hoc correction. (a) Survey of FDA-approved NSAIDs. Brain levels of Aβ were determined after 3 days of oral dosing and compared with controls treated with vehicle alone. All animals were treated with 50 mg/kg per day except for indomethacin, which was dosed at 10 mg/kg per day (#P = 0.051, *P < 0.03, **P < 0.01). A statistically significant 17% reduction in Aβ42 levels is seen in the diclofenac treatment group (n = 8 animals), whereas a nonsignificant trend is noted in the piroxicam treatment group (n = 4), despite the fact that the average decrease in Aβ42 levels is larger (19%). Control values for the untreated Tg2576 mice are 18.5 ± 0.7 pM/gm for Aβ40 and 7.7 ± 0.3 pM/gm for Aβ42. (b) Dose-response studies with R- and S-flurbiprofen. Brain levels of Aβ were determined after 3 days of oral dosing and compared with controls treated with vehicle alone. All of these treatments significantly lowered Aβ42 levels. Treatment with 25 and 50 mg/kg per day of S-flurbiprofen also lowered Aβ40 levels, an effect possibly attributable to toxicity; no effect was seen on Aβ40 with R-flurbiprofen treatment (*P < 0.01, **P < 0.01). (c) Comparison between Aβ42 levels in cell culture and in transgenic mice. Mean inhibition of Aβ42 production is shown in the H4 cell line (in vitro, gray bars) and in TG2576 mice (in vivo, black bars).