Kapoor A.Wang B.-J.WEN-MING HSUChang M.-Y.Liang S.-M.Liao Y.-F.2020-03-052020-03-0520131948-7193https://www.scopus.com/inward/record.uri?eid=2-s2.0-84880381926&doi=10.1021%2fcn400039s&partnerID=40&md5=6d038c6db25ace732743c86855d3057ahttps://scholars.lib.ntu.edu.tw/handle/123456789/470001Retinoic 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.[SDGs]SDG32 (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; Tretinoinjournal article10.1021/cn400039s235309292-s2.0-84880381926