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

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 Abeta42 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 Abeta42 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 Abeta42 secretion from cultured cells. We find that altered arachidonic acid metabolism via NSAID action on cyclooxygenases and lipoxygenases does not alter Abeta42 production. Furthermore, we demonstrate that alterations in activity of peroxisome proliferator-activated receptors, IkappaB kinase beta or nuclear factor kappaB do not affect Abeta42 production. Thus, NSAIDs do not appear to alter Abeta42 production indirectly through previously identified cellular targets and may interact directly with the gamma-secretase complex itself to affect amyloid production.