Retinoid X receptor-alpha mediates (R )-flurbiprofen's effect on the levels of Alzheimer's beta-amyloid.
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 (Abeta). 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 Abeta, especially the more amyloidogenic form Abeta42. 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 Abeta secretion, but at the same time, increases the level of intracellular Abeta. In addition, we find that a nuclear receptor, retinoid X receptor alpha (RXRalpha), can regulate Abeta generation and that down-regulation of RXRalpha significantly increases Abeta secretion. We also show that (R)-flurbiprofen can interfere with the interaction between RXRalpha and 9-cis-retinoid acid, and that 9-cis-retinoid acid decreases (R)-flurbiprofen's reduction of Abeta secretion. Moreover, the modulation effect of (R)-flurbiprofen on Abeta is abolished upon RXRalpha down-regulation. Together, these results suggest that RXRalpha can regulate Abeta generation and is also required for (R)-flurbiprofen-mediated Abeta generation.
You
Xiaoqing
X
Institute for Biomedical Research and School of Life Sciences, Xiamen University, Xiamen, China.
Zhang
Yun-Wu
YW
Chen
Yaomin
Y
Huang
Xiumei
X
Xu
Raymond
R
Cao
Xihua
X
Chen
Jiebo
J
Liu
Yun
Y
Zhang
Xiaokun
X
Xu
Huaxi
H
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D019921:Biotinylation; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005480:Flurbiprofen / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009842:Oligopeptides; C449186:PS1 antigen; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D047488:Retinoid X Receptors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse