All-trans-retinoic Acid Reduces BACE1 Expression under Inflammatory Conditions via Modulation of Nuclear Factor kappa B (NF kappa B) Signaling

作者：Wang, Ruishan^*; Chen, Shaoya; Liu, Yingchun; Diao, Shiyong; Xue, Yueqiang; You, Xiaoqing; Park, Edwards A.; Liao, Francesca-Fang

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290(37): 22532-22542.

DOI：10.1074/jbc.M115.662908

• RELATIONAL MEMORY DEFICIT
• TUMOR-NECROSIS-FACTOR
• VITAMIN-A-DEFICIENCY
• ALZHEIMERS-DISEASE
• AMYLOID-BETA
• DIFFERENTIAL REGULATION
• THERAPEUTIC STRATEGY
• PROMOTER ACTIVITY
• RECEPTORS
• INHIBITION

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-beta (A beta) deposition and its associated inflammatory response are hallmarks in sporadic AD brains. Elevated expression and activity of beta-secretase 1 (BACE1), the rate-limiting enzyme responsible for the beta-cleavage of amyloid precursor proteins to A beta 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 A beta. 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 NF kappa B binding site in BACE1 promoter abolished the suppressive effect of atRA. Furthermore, atRA disrupted LPS-induced nuclear translocation of NF kappa B 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 NF kappa B signaling.

• 出版日期2015-9-11
• 单位福建医科大学