Lack of specific amyloid-β(1-42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures

Recent studies indicating that some nonsteroidal anti-inflammatory drugs (NSAIDs) selectively modulate gamma-secretase cleavage of amyloid precursor protein (APP) while sparing Notch processing have generated interest in discovery of novel gamma-secretase modulators with the "NSAID-like" efficacy profile. The objective of the present studies was to compare the efficacy of a subset of NSAIDs with previously reported classical gamma-secretase inhibitors LY-411575 [N-2-[(2S)-2-(3,5-difluorophenyl)-2- hydroxyethanoyl]-N-1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H- dibenzo[b, d] azepin-7-yl]-L-alaninamide] and DAPT [N-[N( 3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester] in Tg2576 mice. Flurbiprofen ( 10 and 25 mg/kg/day) was overtly toxic and elicited significant ( but nonselective) reductions in both Abeta(1-40) and Abeta(1-42) in the plasma in one of two studies. Flurbiprofen also produced a small reduction in Abeta(1-40) in the cortex at 25 mg/kg/day but did not affect Abeta levels in hippocampus or cerebrospinal fluid. Ibuprofen and sulindac sulfide were neither overtly toxic nor efficacious at doses up to 50 mg/kg/day. The effects of NSAIDs LY-411575 and DAPT were tested in guinea pig embryonic neuronal cultures to determine whether the selective reductions in Abeta(1-42) observed in cell lines overexpressing human mutant APP can be reproduced in a neuronal model of physiological Abeta production and secretion. Flurbiprofen and sulindac nonselectively reduced Abeta(1-40) and Abeta(1- 42) at concentrations greater than or equal to125 muM, although cytotoxicity was noted at greater than or equal to250 muM sulindac. Ibuprofen had no effect at concentrations up to 500 muM. In contrast, DAPT and LY-411575 potently and completely inhibited Abeta(1- 40), Abeta(1- 42), and Abeta(1-38) in the absence of cytotoxicity. The divergence of the present data from published reports raises the need to examine the conditions necessary to perceive selective Abeta( 1- 42) reduction by NSAIDs in neuronal tissue.