title: All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor κB (NFκB) signaling.
abstract: Insulin resistance and neuroinflammation have emerged as two likely key contributors in the pathogenesis of Alzheimer disease (AD), especially in those sporadic AD cases compromised by diabetes or cardiovascular disease. Amyloid-β (Aβ) deposition and its associated inflammatory response are hallmarks in sporadic AD brains. Elevated expression and activity of β-secretase 1 (BACE1), the rate-limiting enzyme responsible for the β-cleavage of amyloid precursor proteins to Aβ peptides, are also observed in sporadic AD brains. Previous studies have suggested that there is therapeutic potential for retinoic acid in treating neurodegeneration based on decreased Aβ. Here we discovered that BACE1 expression is elevated in the brains of both Tg2576 transgenic mice and mice on high fat diets. These conditions are associated with a neuroinflammatory response. We found that administration of all-trans-retinoic acid (atRA) down-regulated the expression of BACE1 in the brains of Tg2576 mice and in mice fed a high fat diet. Moreover, in LPS-treated mice and cultured neurons, BACE1 expression was repressed by the addition of atRA, correlating with the anti-inflammatory efficacy of atRA. Mutations of the NFκB binding site in BACE1 promoter abolished the suppressive effect of atRA. Furthermore, atRA disrupted LPS-induced nuclear translocation of NFκB and its binding to BACE1 promoter as well as promoting the recruitment of the corepressor NCoR. Our findings indicate that atRA represses BACE1 gene expression under inflammatory conditions via the modulation of NFκB signaling.
authors.affiliation: From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, rwang11@uthsc.edu.
authors.forename: Ruishan
authors.initials: R
authors.lastname: Wang
authors.affiliation: From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Shaoya
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Diao
authors.affiliation: From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Yueqiang
authors.initials: Y
authors.lastname: Xue
authors.affiliation: the Division of Cell Biology and Genetics, Fujian Medical University, Fuzhou 350004, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: You
authors.affiliation: From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the Department of Veterans Affairs Medical Center, Memphis, Tennessee 38163, and.
authors.forename: Edwards A
authors.initials: EA
authors.lastname: Park
authors.affiliation: From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, fliao@uthsc.edu.
authors.forename: Francesca-Fang
authors.initials: FF
authors.lastname: Liao
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D004041:Dietary Fats; D016328:NF-kappa B; D014212:Tretinoin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer disease; NFkappa B (NFKB); beta-secretase 1 (BACE1); gene transcription; retinoic acid; retinoid signaling