title: The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of kappa B kinase, and NF kappa B, do not reduce amyloid beta 42 production.
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.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California 921093, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sagi
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Jason
authors.initials: J
authors.lastname: Eriksen
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors