All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor κB (NFκB) signaling

Ruishan Wang, Shaoya Chen, Yingchun Liu, Shiyong Diao, Yueqiang Xue, Xiaoqing You, Edwards Park, Francesca-Fang Liao

Research output: Contribution to journalArticle

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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 sporadicADbrains. 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 LPStreated mice and cultured neurons, BACE1 expression was repressed by the addition of atRA, correlating with the antiinflammatory 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.

Original languageEnglish (US)
Pages (from-to)22532-22542
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number37
DOIs
StatePublished - Sep 11 2015

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Tretinoin
Modulation
Brain
Alzheimer Disease
High Fat Diet
Nutrition
Fats
Co-Repressor Proteins
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Medical problems
Amyloid
Gene expression
Transgenic Mice
Neurons
Insulin Resistance
Anti-Inflammatory Agents
Cardiovascular Diseases
Binding Sites
Insulin

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor κB (NFκB) signaling. / Wang, Ruishan; Chen, Shaoya; Liu, Yingchun; Diao, Shiyong; Xue, Yueqiang; You, Xiaoqing; Park, Edwards; Liao, Francesca-Fang.

In: Journal of Biological Chemistry, Vol. 290, No. 37, 11.09.2015, p. 22532-22542.

Research output: Contribution to journalArticle

Wang, Ruishan ; Chen, Shaoya ; Liu, Yingchun ; Diao, Shiyong ; Xue, Yueqiang ; You, Xiaoqing ; Park, Edwards ; Liao, Francesca-Fang. / All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor κB (NFκB) signaling. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 37. pp. 22532-22542.
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