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Experimental Genetics Group
J Neurosci. 2003 Oct 29;23(30):9796-804. Sastre M1, Dewachter I2, Landreth GE3, Willson TM4, Klockgether T1, van Leuven F2, Heneka MT1. 1Department of Neurology, University of Bonn, Bonn, Germany. 2Department of Human Genetics, Experimental Genetics Group, Leuven, Belgium. 3Alzheimer Laboratory, Case Western Reserve University, Cleveland, Ohio. 4GlaxoSmithKline, Discovery Research, North Carolina. Long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for Alzheimer's disease (AD). To determine the mechanisms by which inflammation affects AD and how NSAIDs protect against it, we stimulated neuroblastoma cells stably transfected with amyloid precursor protein (APP) with proinflammatory cytokines, which increased the secretion of amyloid-beta and APP ectodomain. Addition of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, or cotransfection with PPARgamma cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARgamma antagonists. Finally, we observed that the mRNA levels, expression, and enzymatic activity of beta-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate beta-secretase, and NSAIDs inhibit this effect through PPARgamma.  FULL TEXT |
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