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

Abstract

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...

Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations

“…Moreover, the PPARα-dependent inhibitory effect of fenofibrate on cancer cell motility has been previously demonstrated (18). However, a PPARα-independent effect of fenofibrate on cell membrane rigidity was noted (19), while both its PPARα-dependent (10,20) and PPARα-independent (21) effects on the accumulation of reactive oxygen species (ROS) were observed. Thus, the question arises concerning the possible involvement of ROS-dependent mechanisms of fenofibrate on cell properties which determine cancer progression, such as cell motility and GJIC.…”

“…For instance, fenofibrate increases cell membrane rigidity imitating the action of cholesterol (19). Membrane microviscosity was also found to affect cell motility and the activity of cell membraneassociated growth factor receptors (33).…”

“…To elucidate the mechanisms involved in the inhibitory effect of fenofibrate on DU-145 cell motility, we investigated the role of PPARα receptors, plasma membrane fluidity (19) and ROS metabolism (10,17) in this process. Cultivation of DU-145 cells in the presence of 10 µM Gw9662, which effectively inhibits both PPARγ and PPARα (32), did not restore the motility of DU-145 cells inhibited by fenofibrate ( Fig.…”

Effects of the non-steroidal anti-inflammatory drug celecoxib on cholesterol containing distearoyl phosphatidylcholine membranes

“…Walter et al [32] showed that CLX is localized at the interfacial region of 1-palmitoyl-2-oleoylsn-glycero-3-phosphocholine (POPC) -cholesterol membranes using small angle X-ray diffraction. In other studies, using fluorescence anisotropy technique, CLX has been shown to decrease membrane fluidity in a mouse neuroblastoma cell line N2a [10] and decrease in membrane fluidity in egg phosphatidylcholine model membranes [27]. In our previous study, using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC), we have found that CLX exerts opposing effects on membrane order in a concentration dependent manner and it decreases the fluidity of the membrane at all concentrations.…”

“…In addition, some COX independent mechanisms, such as membrane dynamics and structure, have also been suggested for its activity [10]. It was proposed that celecoxib induces formation of amyloid-β peptides by ordering the cellular membranes and thus changing the activity of membrane bound proteins, especially β-and γ-secretase.…”