Nuclear receptor signaling in BACE1 gene repression under neuroinflammation

神经炎症下 BACE1 基因抑制中的核受体信号转导

• 批准号: 8560124
• 负责人: Francesca-Fang Liao
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8560124
• 关键词: Acids; Acute; Age; Agonist; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animal Model; Beryllium; Brain; Caloric Restriction; Cardiovascular Diseases; Cholesterol; Chronic; Clinical Trials; Cognitive deficits; Combined Modality Therapy; Data; Diabetes Mellitus; Diet; Elements; Enzymes; Fatty acid glycerol esters; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Hypoxia; Impaired cognition; In Vitro; Indium; Inflammation; Inflammatory; Insulin Resistance; Intake; Isomerism; Ligands; Link; Mediating; Metabolic; Metabolic stress; Milk; Modeling; Molecular; Mus; NF-kappa B; Neurons; Nuclear; Nuclear Receptors; Nutritional; PPAR gamma; Pathogenesis; Peptides; Peroxisome Proliferator-Activated Receptors; Prosencephalon; Protein Isoforms; Proteins; RNA; RXR; Receptor Signaling; Recruitment Activity; Regulation; Regulatory Pathway; Resistance; Response Elements; Retinoic Acid Receptor; Retinoids; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; TNF gene; Testing; Transactivation; Transcription Coactivator; Translations; Up-Regulation; Vitamin Deficiency; Work; amyloidogenesis; base; beta secretase; beta-site APP cleaving enzyme 1; cohort; cytokine; feeding; gene repression; in vivo; insight; insulin signaling; mRNA Expression; middle age; mouse model; neuroinflammation; novel; overexpression; prevent; promoter; public health relevance; receptor

DESCRIPTION (provided by applicant): Age-associated metabolic risk factor(s) or nutritional imbalances, such as excessive fat and cholesterol intake or hypovitaminosis, are often linked to increased amyloidogenesis, as seen in late-onset sporadic Alzheimer's disease (SAD). Elevated expression of beta-secretase BACE1 is observed in SAD brains. In cultured neuronal models, we show that BACE1 transcription is upregulated through metabolic risk factors. Overexpression of the PPARgamma coactivator (PGC-1) a key metabolic regulator or all-trans retinoid acid (atRA) can reduce the elevated BACE1 expression resulting from inflammation induced by a high fat high cholesterol diet (HFD). Markedly increased RNA and protein levels of BACE1 were also found in the mouse forebrains fed HFD for 2 months; 2-months of treatment with atRA restored BACE1 mRNA and expression after HFD feeding. Given the increasingly recognized importance of retinoid signaling in AD and the promise of retinoid-based therapies, our long-term goal is to fully characterize the beneficial effects and the underlying molecular mechanisms of atRA in mitigating neuroinflammation and amyloidogenesis. In this application, we will test the hypotheses first that atRA suppresses BACE1 expression via recruitment of liganded RARs to the promoter, secondly that coregulators including PGC-1 and nuclear corepressors participate in the transcriptional repression and finally that atRA and RARs interfere with the NF-gammaB mediated induction of BACE1. Two aims are proposed to investigate 1) the molecular mechanism underlying the negative regulation of BACE1 transcription by atRA and 2) the mechanisms by which atRA modulates NF-gammaB activity upon inflammation. We will employ both in vitro cellular (TNFalpha +LPS) as well as animal models representing acute and chronic neuroinflammation (systemic LPS, HFD etc). Given the emerging role of aberrantly activated NF-gammaB in AD pathogenesis, studying atRA's regulation of this molecule is of potential broad impact not only for BACE1 gene regulation but also in large cohorts of NF-gammaB-sensitive genes in AD brains. Although BACE1 regulation has been extensively studied under hypoxic and metabolic stressed conditions including ROS, its upregulation under neuroinflammatory conditions is largely understudied. Hence, our focus of investigating its negative regulation by nuclear receptors upon inflammation is of high novelty. Successful completion of this project will be instrumental for future pursuing potential combination therapy between agents promoting retinoid signaling and insulin- sensitization (PPARgamma agonists etc).

描述（由申请人提供）：与年龄相关的代谢危险因素或营养失衡，例如脂肪和胆固醇摄入过多或维生素缺乏症，通常与淀粉样蛋白生成增加有关，如晚发散发性阿尔茨海默病 (SAD) 中所见。在 SAD 大脑中观察到 β-分泌酶 BACE1 表达升高。在培养的神经元模型中，我们发现 BACE1 转录通过代谢危险因素上调。 PPARgamma 共激活剂 (PGC-1)（一种关键的代谢调节剂）或全反式维甲酸 (atRA) 的过度表达可以减少由高脂肪高胆固醇饮食 (HFD) 诱导的炎症引起的 BACE1 表达升高。在喂食 HFD 2 个月的小鼠前脑中，BACE1 的 RNA 和蛋白质水平也显着增加； HFD 喂养后，2 个月的 atRA 治疗恢复了 BACE1 mRNA 和表达。鉴于人们日益认识到类视黄醇信号传导在 AD 中的重要性以及基于类视黄醇的治疗的前景，我们的长期目标是充分表征 atRA 在减轻神经炎症和淀粉样蛋白生成方面的有益作用和潜在分子机制。在本申请中，我们将首先测试以下假设：atRA 通过将配体 RAR 募集到启动子来抑制 BACE1 表达，其次，包括 PGC-1 和核辅阻遏物在内的共调节子参与转录抑制，最后，atRA 和 RAR 干扰 NF-gammaB 介导的 BACE1 诱导。提出了两个目标来研究 1) atRA 对 BACE1 转录负调节的分子机制和 2) atRA 在炎症时调节 NF-gammaB 活性的机制。我们将采用体外细胞（TNFα + LPS）以及代表急性和慢性神经炎症（全身性 LPS、HFD 等）的动物模型。鉴于异常激活的 NF-gammaB 在 AD 发病机制中的新作用，研究 atRA 对该分子的调节不仅对 BACE1 基因调节，而且对 AD 大脑中大量 NF-gammaB 敏感基因具有潜在的广泛影响。尽管 BACE1 在缺氧和代谢应激条件下（包括 ROS）的调节已被广泛研究，但其在神经炎症条件下的上调在很大程度上还没有得到充分研究。因此，我们研究核受体对炎症的负调节的重点具有很高的新颖性。该项目的成功完成将有助于未来寻求促进类维生素A信号传导和胰岛素增敏的药物（PPARγ激动剂等）之间的潜在联合治疗。