title: Retinoic acid-elicited RARα/RXRα signaling attenuates Aβ production by directly inhibiting γ-secretase-mediated cleavage of amyloid precursor protein.
abstract: 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.
authors.affiliation: Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology , Academia Sinica, Taipei, Taiwan.
authors.forename: Arun
authors.initials: A
authors.lastname: Kapoor
authors.forename: Bo-Jeng
authors.initials: BJ
authors.lastname: Wang
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.forename: Ming-Yun
authors.initials: MY
authors.lastname: Chang
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Liang
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D020935:MAP Kinase Signaling System; D047490:Retinoid X Receptor alpha / Q000494:pharmacology*; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047490:Retinoid X Receptor alpha; D014212:Tretinoin; D053829:Amyloid Precursor Protein Secretases