Nonsteroidal Anti-inflammatory Drugs and Peroxisome Proliferator-activated Receptor-gamma Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein Through Regulation of Beta-secretase

Overview

Journal J Neurosci

Specialty Neurology

Date 2003 Oct 31

PMID 14586007

Citations 150

Authors

Magdalena Sastre

Ilse Dewachter

Gary E Landreth

Timothy M Willson

Thomas Klockgether

Fred Van Leuven

Michael T Heneka

Affiliations

Soon will be listed here.

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-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.

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