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 A Park,Francesca-Fang Liao

doi:10.1074/jbc.m115.662908

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.

Highlights

BACE1 is the rate-limiting enzyme in the cleavage of amyloid precursor protein to A␤ peptides
We found that administration of all-trans-retinoic acid down-regulated the expression of BACE1 in the brains of Tg2576 mice and in mice fed a high fat diet
Results all-trans-retinoic acid (atRA) Treatment Reduces Cortical BACE1 Expression in Tg2576 and High fat diet (HFD) Mice—We tested the effect of systemic administration of atRA on BACE1 expression in symptomatic Tg2576 mice overexpressing the transgene of human Swedish mutant of APP695

Summary

Introduction

BACE1 is the rate-limiting enzyme in the cleavage of amyloid precursor protein to A␤ peptides. Conclusion: Retinoic acid suppresses aspects of neuroinflammation in rodent models of Alzheimer disease including elevated BACE1 transcription. Elevated expression and activity of ␤-secretase 1 (BACE1), the rate-limiting enzyme responsible for the ␤-cleavage of amyloid precursor proteins to A␤ peptides, are observed in sporadic AD brains. 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. Our findings indicate that atRA represses BACE1 gene expression under inflammatory conditions via the modulation of NF␬B signaling

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Results

Conclusion