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: 8690189
• 负责人: Francesca-Fang Liao
• 金额: $ 18.56万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690189
• 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; 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; peptide A; 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(申请人提供)：年龄相关的代谢风险因素(S)或营养失衡，如过多的脂肪和胆固醇摄入或维生素缺乏，通常与淀粉样蛋白生成增加有关，如晚发性散发性阿尔茨海默病(SAD)。在SAD脑中观察到β-分泌酶BACE1的表达增加。在培养的神经元模型中，我们发现BACE1转录通过代谢危险因子上调。过表达PPAR-γ共激活因子(PGC-1)或全反式维甲酸(AtRA)可以降低高脂高胆固醇饮食(HFD)诱导的炎症引起的BACE1表达升高。给予HFD 2个月的小鼠前脑中BACE1的RNA和蛋白水平也明显升高，给予atRA治疗2个月后，BACE1的mRNA和表达有所恢复。鉴于维甲酸信号在阿尔茨海默病中的重要性以及维甲酸治疗的前景，我们的长期目标是充分研究全反式维甲酸在减轻神经炎症和淀粉样变方面的有益作用和潜在的分子机制。在本应用中，我们将首先检验假设，即atRA通过将连接的RARs招募到启动子来抑制BACE1的表达，其次，包括PGC-1和核转录抑制因子在内的共同调节因子参与转录抑制，最后atRA和RARs干扰NF-GammaB介导的BACE1的诱导。本研究旨在探讨atRA负性调控BACE1转录的分子机制和atRA调节炎症反应中NF-GammaB活性的机制。我们将使用体外细胞(TNFpha+内毒素)以及代表急性和慢性神经炎的动物模型(全身性内毒素、HFD等)。鉴于异常激活的NF-GammaB在AD发病机制中的作用，研究全反式维甲酸对该分子的调控不仅对BACE1基因的调控具有潜在的广泛影响，而且对AD脑中大量的NF-GammaB敏感基因也具有潜在的广泛影响。虽然BACE1在包括ROS在内的低氧和代谢应激条件下的调节已经被广泛研究，但在神经炎症条件下它的上调在很大程度上还没有被研究。因此，我们研究核受体对炎症的负调控具有很高的新颖性。该项目的成功完成将有助于未来寻求促进视黄醇信号转导和胰岛素增敏的药物(PPAR、伽马激动剂等)之间的潜在联合治疗。