Retinoid X receptor-α mediates (R )-flurbiprofen's effect on the levels of Alzheimer's β-amyloid

• Published in: Journal of neurochemistry 2009-10, Vol.111 (1), p.142-149
• Main Authors: You, Xiaoqing, Zhang, Yun-wu, Chen, Yaomin, Huang, Xiumei, Xu, Raymond, Cao, Xihua, Chen, Jiebo, Liu, Yun, Zhang, Xiaokun, Xu, Huaxi
• Format: Article
• Language: English
• Subjects: (R)-flurbiprofen; Adult and adolescent clinical studies; Alzheimer disease; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Biological and medical sciences; Biotinylation; Cell Line, Tumor; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flurbiprofen - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Immunoprecipitation; Medical sciences; Mice; Neurology; non-steroidal anti-inflammatory drug; Oligopeptides - genetics; Oligopeptides - metabolism; Organic mental disorders. Neuropsychology; Peptide Fragments - metabolism; Protein Binding - drug effects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Notch - genetics; Receptors, Notch - metabolism; retinoid X receptor α; Retinoid X Receptors - genetics; Retinoid X Receptors - metabolism; RNA, Small Interfering - metabolism; Transfection; β-amyloid
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06312.x

Alzheimer's disease (AD) is characterized by the formation of extracellular senile plaques in the brain, whose major component is a small peptide called β-amyloid (Aβ). 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 Aβ, especially the more amyloidogenic form Aβ42. 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 Aβ secretion, but at the same time, increases the level of intracellular Aβ. In addition, we find that a nuclear receptor, retinoid X receptor α (RXRα), can regulate Aβ generation and that down-regulation of RXRα significantly increases Aβ secretion. We also show that (R)-flurbiprofen can interfere with the interaction between RXRα and 9-cis-retinoid acid, and that 9-cis-retinoid acid decreases (R)-flurbiprofen's reduction of Aβ secretion. Moreover, the modulation effect of (R)-flurbiprofen on Aβ is abolished upon RXRα down-regulation. Together, these results suggest that RXRα can regulate Aβ generation and is also required for (R)-flurbiprofen-mediated Aβ generation.