The Non-cyclooxygenase Targets of Non-steroidal Anti-inflammatory Drugs, Lipoxygenases, Peroxisome Proliferator-activated Receptor, Inhibitor of κB Kinase, and NFκB, Do Not Reduce Amyloid β42 Production

Department of Neurosciences, University of California San Diego, La Jolla, California 921093, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2003; 278(34):31825-30. DOI: 10.1074/jbc.M303588200
Source: PubMed

ABSTRACT Epidemiological evidence suggests that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of Alzheimer's disease. Recently, NSAIDs have been shown to decrease amyloid pathology in a transgenic mouse model of Alzheimer's disease. This benefit may be partially attributable to the ability of NSAIDs to selectively reduce production of the amyloidogenic A beta 42 peptide in both cultured cells and transgenic mice. Although this activity does not appear to require the action of cyclooxygenases in cultured cells, it is not known whether other NSAID-sensitive targets contribute to this A beta 42 effect. In this study, we have used both pharmacological and genetic means to determine if other known cellular targets of NSAIDs could mediate the reduction in A beta 42 secretion from cultured cells. We find that altered arachidonic acid metabolism via NSAID action on cyclooxygenases and lipoxygenases does not alter A beta 42 production. Furthermore, we demonstrate that alterations in activity of peroxisome proliferator-activated receptors, I kappa B kinase beta or nuclear factor kappa B do not affect A beta 42 production. Thus, NSAIDs do not appear to alter A beta 42 production indirectly through previously identified cellular targets and may interact directly with the gamma-secretase complex itself to affect amyloid production.

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    • "Some modulators exhibit non-linear or non-competitive kinetics, and may act at structural modification or at allosteric sites of c-SC, including sulfonamides, benzodiazopenes , Liþ, casein kinase inhibitors, or kinase inhibitors (Tian et al., 2002; Churcher et al., 2003; Owens et al., 2003; Phiel et al., 2003; Flajolet et al., 2007). Long-term administration of non-steroid anti-inflammatory drugs, showing beneficial effects, was believed to target allosteric sites of c-SC or nucleotide binding sites within c-SC, reducing amyloidogenesis while sparing the Notch signaling pathway (Eriksen et al., 2003; Sagi et al., 2003; Zhou et al., 2003; Fraering et al., 2005). At least two promising c-SC inhibitors have been clinically tested. "
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    • "The effectiveness of flurbiprofen, ibuprofen and sulindac sulfide for lowering A production has been confirmed using primary neurons as the target cell [56], but this study did not report the specific effect to A(42) as these agents were effective at lowering A(40) production as well. These authors concluded that the mechanism of action of these NSAIDs is not related to their COX, lipoxygenase, NFB or IB inhibiting-, or PPAR-activating-, properties, as specific agents for these targets did not affect A levels in the assays used [151]. The effect appeared to be due to inhibition of Rho and a Rho-kinase [199]. "
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    • "Because epidemiological studies indicate that long-term intake of non-steroidal anti-inflammatory drugs reduces the risk of developing AD (in't Veld et al., 2001), one of the proposed approaches for AD therapy considers the use of molecules inhibiting neuroinflammatory phenomena. Indeed, a subset of non-steroidal anti-inflammatory drugs also affects amyloid production, by reducing the secretion of Ab42 from cultured cells, independently of their effects on cyclooxygenase activity (Weggen et al., 2001; Sagi et al., 2003). Their direct interaction with the c-secretase complex in cell-free assays (Takahashi et al., 2003; Weggen et al., 2003) has further suggested that they may act by preventing neurodegeneration besides contrasting inflammatory response. "
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