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 Ca 2ϩ -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.According to the amyloid cascade hypothesis, the formation of amyloid- peptides derived from the amyloid precursor protein (APP) is causally associated with the pathogenesis of Alzheimer's disease (AD). This hypothesis is substantiated by several lines of evidence: 1) amyloid- peptides are found accumulated in extracellular plaques in the brains of patients with AD; 2) several genetic predispositions exist with mutations concerning APP itself or components of the ␥-secretase complex (presenilins), one of the APP processing enzymes; 3) increased APP dosage by triplication of APP gene locus in Down syndrome (trisomy 21) or by APP gene locus duplication and promoter mutations that increase APP expression promote the progression of AD; and 4) the toxicity of aggregated amyloid- peptides is clearly documented in vitro (Hardy and Selkoe, 2002;Rovelet-Lecrux et al., 2006;Theuns et al., 2006). Besides few familial forms with the aforementioned mutations, most cases of AD are age-associated and sporadic; therefore, other factors promoting the formation of amyloid- peptides over time have to be considered. In this regard, alterations in the lipid metabolism, particularly disturbances of cholesterol homeostasis, may represent high-risk factors (Shobab et al., 2005). Because am...