Retinoid X receptor-alpha mediates (R )-flurbiprofen's effect on the levels of Alzheimer's beta-amyloid
- 生命科学－已发表论文 
Alzheimer's disease (AD) is characterized by the formation of extracellular senile plaques in the brain, whose major component is a small peptide called beta-amyloid (A beta). Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been found beneficial for AD and several reports suggest that NSAIDs reduce the generation of A beta, especially the more amyloidogenic form A beta 42. However, the exact mechanism underlying NSAIDs' effect on AD risk remains largely inconclusive and all clinical trials using NSAIDs for AD treatment show negative results so far. Recent studies have shown that some NSAIDs can bind to certain nuclear receptors, suggesting that nuclear receptors may be involved in NSAID's effect on AD risk. Here we find that (R)-flurbiprofen, the R-enantiomer of the racemate NSAID flurbiprofen, can significantly reduce A beta secretion, but at the same time, increases the level of intracellular A beta. In addition, we find that a nuclear receptor, retinoid X receptor alpha (RXR alpha), can regulate A beta generation and that down-regulation of RXR alpha significantly increases A beta secretion. We also show that (R)-flurbiprofen can interfere with the interaction between RXR alpha and 9-cis-retinoid acid, and that 9-cis-retinoid acid decreases (R)-flurbiprofen's reduction of A beta secretion. Moreover, the modulation effect of (R)-flurbiprofen on A beta is abolished upon RXR alpha down-regulation. Together, these results suggest that RXR alpha can regulate A beta generation and is also required for (R)-flurbiprofen-mediated A beta generation.
CitationJournal of Neurochemistry，Volume111,Issue1,Pages142-149,October2009