https://scholars.lib.ntu.edu.tw/handle/123456789/470001
標題: | Retinoic acid-elicited RARα/RXRα signaling attenuates aβ production by directly inhibiting γ-secretase-mediated cleavage of amyloid precursor protein | 作者: | Kapoor A. Wang B.-J. WEN-MING HSU Chang M.-Y. Liang S.-M. Liao Y.-F. |
公開日期: | 2013 | 卷: | 4 | 期: | 7 | 起(迄)頁: | 1093-1100 | 來源出版物: | ACS Chemical Neuroscience | 摘要: | Retinoic acid (RA)-elicited signaling has been shown to play critical roles in development, organogenesis, and the immune response. RA regulates expression of Alzheimer's disease (AD)-related genes and attenuates amyloid pathology in a transgenic mouse model. In this study, we investigated whether RA can suppress the production of amyloid-β (Aβ) through direct inhibition of γ-secretase activity. We report that RA treatment of cells results in significant inhibition of γ-secretase-mediated processing of the amyloid precursor protein C-terminal fragment APP-C99, compared with DMSO-treated controls. RA-elicited signaling was found to significantly increase accumulation of APP-C99 and decrease production of secreted Aβ40. In addition, RA-induced inhibition of γ-secretase activity was found to be mediated through significant activation of extracellular signal-regulated kinases (ERK1/2). Treatment of cells with the specific ERK inhibitor PD98059 completely abolished RA-mediated inhibition of γ-secretase. Consistent with these findings, RA was observed to inhibit secretase-mediated proteolysis of full-length APP. Finally, we have established that RA inhibits γ-secretase through nuclear retinoic acid receptor-α (RARα) and retinoid X receptor-α (RXRα). Our findings provide a new mechanistic explanation for the neuroprotective role of RA in AD pathology and add to the previous data showing the importance of RA signaling as a target for AD therapy. ? 2013 American Chemical Society. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84880381926&doi=10.1021%2fcn400039s&partnerID=40&md5=6d038c6db25ace732743c86855d3057a https://scholars.lib.ntu.edu.tw/handle/123456789/470001 |
ISSN: | 1948-7193 | DOI: | 10.1021/cn400039s | SDG/關鍵字: | 2 (2 amino 3 methoxyphenyl)chromone; amyloid beta protein; amyloid precursor protein; dimethyl sulfoxide; gamma secretase; mitogen activated protein kinase 1; retinoic acid; retinoic acid receptor alpha; retinoid X receptor alpha; article; controlled study; embryo; enzyme activation; enzyme activity; enzyme inhibition; enzyme repression; human; human cell; priority journal; protein cleavage; protein degradation; signal transduction; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Cells, Cultured; Humans; MAP Kinase Signaling System; Retinoid X Receptor alpha; Signal Transduction; Tretinoin |
顯示於: | 醫學系 |
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