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Cholesterol-Like Effects of Selective Cyclooxygenase Inhibitors and Fibrates on Cellular Membranes and Amyloid- Production

From the Department of Pathobiochemistry, Medical School, Johannes Gutenberg University, Mainz, Germany

Strong evidence suggests a mechanistic link between cholesterol metabolism and the formation of amyloid- peptides, the principal constituents of senile plaques found in the brains of patients with Alzheimer's disease. Here, we show that several fibrates and diaryl heterocycle cyclooxygenase inhibitors, among them the commonly used drugs fenofibrate and celecoxib, exhibit effects similar to those of cholesterol on cellular membranes and amyloid precursor protein (APP) processing. These drugs have the same effects on membrane rigidity as cholesterol, monitored here by an increase in fluorescence anisotropy. The effect of the drugs on cellular membranes was also reflected in the inhibitory action on the sarco(endo)plasmic reticulum Ca²⁺-ATPase, which is known to be inhibited by excess ordering of membrane lipids. The drug-induced decrease of membrane fluidity correlated with an increased association of APP and its -site cleaving enzyme BACE1 with detergent-resistant membranes (DRMs), which represent membrane clusters of substantial rigidity. DRMs are hypothesized to serve as platforms for the amyloidogenic processing of APP. According to this hypothesis, both cholesterol and the examined compounds stimulated the -secretase cleavage of APP, resulting in a massive increase of secreted amyloid- peptides. The membrane-ordering potential of the drugs was observed in a cell-free assay, suggesting that the amyloid- promoting effect was analog to cholesterol due to primary effect on membrane rigidity. Because fenofibrate and celecoxib are widely used in humans as hypolipidemic drugs for prevention of atherosclerosis and as anti-inflammatory drugs against arthritis, possible side effects should be considered upon long-term clinical application.

Address correspondence to: Dr. Christian Behl, Institute for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, Medical School, Duesbergweg 6, 55099 Mainz, Germany. E-mail: cbehl{at}unimainz.de