Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-γ Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of β-Secretase

Abstract

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-β and APP ectodomain. Addition of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-γ (PPARγ) agonists, or cotransfection with PPARγ cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARγ antagonists. Finally, we observed that the mRNA levels, expression, and enzymatic activity of β-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate β-secretase, and NSAIDs inhibit this effect through PPARγ.