Effects of binge ethanol on neuroinflammation and neurodegeneration with high fat diets

暴饮乙醇对高脂肪饮食引起的神经炎症和神经变性的影响

• 批准号: 10668068
• 负责人: SULIE L. CHANG
• 金额: $ 39.19万
• 依托单位: SETON HALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668068
• 关键词: Abbreviations; Adaptor Signaling Protein; Adipose tissue; Affect; Alcohol consumption; Alcohols; Amygdaloid structure; Amyloid beta-Protein Precursor; Animal Model; Anti-Inflammatory Agents; Antibodies; Atrophic; Attenuated; Bioinformatics; Blood alcohol level measurement; Brain; CX3CL1 gene; Calcium Binding; Cell membrane; Cerebral cortex; Chronic; Development; Diet; Disease; Disease Progression; Docosahexaenoic Acids; Docosahexaenoic acid supplement; Elderly; Essential Fatty Acids; Ethanol; Exhibits; Fatty Acids; Fatty acid glycerol esters; HIV; HIV-1; HIV/AIDS; High Fat Diet; Hippocampus; Hypothalamic structure; Immune; Immunofluorescence Immunologic; Inflammation; Knowledge; Laboratories; Licensing; Ligands; Link; Mediating; Mediator; Microglia; Molecular; Mus; N-3 polyunsaturated fatty acid; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Nutrient; Obesity; Outcome Study; Pathology; Pathway Analysis; Patients; Pattern; Polyunsaturated Fatty Acids; Prevalence; Production; Property; Proteins; Rat Transgene; Rattus; Reporting; Research; Risk Factors; Saturated Fatty Acids; Solid; Stains; Testing; Therapeutic; United States; alcohol effect; antiretroviral therapy; attenuation; binge drinking; cerebral atrophy; chemokine; clinically relevant; combinatorial; diet-induced obesity; drinking; feeding; fluoro jade; human model; in vivo; inflammatory marker; ionization; knowledge base; locus ceruleus structure; mild cognitive impairment; mouse model; neuroinflammation; neuron component; neuroprotection; prevent; systemic inflammatory response; transcriptome; transcriptome sequencing; white matter

Abstract: Obesity has been associated with neuroinflammation and neurodegeneration. Binge drinking (BD) has also been reported to lead to neuroinflammation and brain atrophy. Moreover, our bioinformatics analysis using Ingenuity Pathway Analysis (IPA) licensed from QIAGEN confirmed that ethanol (EtOH) and obesity induce neuroinflammation. Studies have suggested alcohol and obesit disease (AD) with neuroinflammation and neurodegeneration as the central link. We also conducted IPA analysis to examine the paths from alcohol and obesity to AD. Both alcohol and obesity were linked to AD with alcohol exhibiting an overall activation of AD development. These studies also revealed a critical knowledge gap on binge EtOH (BE) augmentation of obesity-induced neuroinflammation and neurodegeneration. As essential nutrients and fundamental components of neuronal and glial cell membranes, n-3 polyunsaturated fatty acids (PUFAs) have been reported with anti-inflammatory properties and beneficial effects in elderly with mild cognitive impairment. Our laboratory used 5-week 3-day each week BE to mimic BD over the weekends and found that docosahexaenoic acid (DHA; 22:6n-3), a PUFA, ameliorates BE-induced inflammation in HIV-1 transgenic rats, an animal model for HIV/AIDS patients on combination antiretroviral therapy. Using IPA, we found that n-3 PUFAs may decrease the production of amyloid precursor protein (APP), a key molecule associated with the onset and progression of AD. Taken these solid premises together, we hypothesize that BE may augment obesity-induced neuroinflammation and neurodegeneration while n-3 PUFAs may attenuate BE-induced neuroinflammation and neurodegeneration. To test these hypotheses, we will use a diet-induced-obesity mouse model by feeding C57BL/6J mice with control 10 kcal% fat diet (CD), DHA-supplemented CD (DCD), 45% kcal% high fat diet (HFD), DHA-supplemented 45 kcal% high fat diet (DHFD) and propose two aims. Aim 1 is to examine the effects of BE on neuroinflammation and neurodegeneration at the cellular level in the brain of mice fed with CD, DCD, HFD, or DHFD with or without BE using immunofluorescence staining and Fluoro-Jade B staining. Aim 2 is to examine the effects of BE on neuroinflammation and neurodegeneration at the molecular level in the brain of mice fed with CD, DCD, HFD, or DHFD with or without BE using RNA-sequencing, antibody arrays, and bioinformatic analysis. These studies are highly significant with clinical relevance. Successful completion of these studies will shed light on whether and how BE may augment obesity-induced neuroinflammation and neurodegeneration and on whether and how n-3 PUFAs may affect BE-induced neuroinflammation and neurodegeneration. The study outcomes shall shift the paradigm regarding interaction between BD and diet-mediated pathologies including characterization of n-3 PUFAs in preventing the onset and progression of AD pathologies.

摘要：肥胖与神经炎症和神经退行性变有关。酗酒(BD) 据报道还会导致神经炎和脑萎缩。此外，我们的生物信息学分析 使用QIAGEN授权的独创性路径分析(IPA)证实乙醇(Etoh)和肥胖诱导 神经炎。研究表明，酒精和顺从 以神经炎症和神经退行性变为中心环节的疾病(AD)。我们还进行了IPA分析 研究从酒精和肥胖到阿尔茨海默病的途径。酒精和肥胖都与饮酒的阿尔茨海默病有关 表现出对AD发展的全面激活。这些研究还揭示了关键的知识差距 过量乙醇(BE)增加肥胖引起的神经炎症和神经变性。作为必不可少的 神经细胞和神经胶质细胞膜的营养物质和基本成分，n-3多不饱和脂肪酸 据报道，多不饱和脂肪酸(PUFAs)对轻度认知障碍的老年人具有抗炎和有益作用 减损。我们实验室使用每周5周3天的BE来模拟周末的BD，并发现 二十二碳六烯酸(DHA；22：6N-3)是一种多不饱和脂肪酸，可减轻BE诱导的HIV-1转基因大鼠的炎症反应。 HIV/AIDS患者联合抗逆转录病毒治疗的动物模型。使用IPA，我们发现n-3 多不饱和脂肪酸可减少淀粉样前体蛋白(APP)的产生，APP是与 阿尔茨海默病的发病和进展。 把这些可靠的前提放在一起，我们假设可能会增加肥胖诱导的 N-3多不饱和脂肪酸可减轻BE诱导的神经炎症和神经变性 神经炎症和神经变性。为了验证这些假设，我们将使用一种饮食诱导的肥胖 以C57BL/6J小鼠为模型，分别喂以对照10kcal%脂肪饲料(CD)、添加DHA的Cd(DCD)、45% KCAL%高脂饲料(HFD)和添加DHA的45Kcal%高脂饲料(DHFD)，并提出两个目标。目标1是 从细胞水平检测Be对小鼠脑神经炎症和神经退行性变的影响 Cd、DCD、HFD或DHFD加或不加BE的免疫荧光染色和荧光素B 染色。目的2从分子水平研究Be对神经炎症和神经退行性变的影响 用RNA测序法、抗体测序法测定Cd、DCD、HFD或DHFD加BE或不加BE的小鼠脑内水平 数组和生物信息学分析。 这些研究具有很高的临床意义。成功完成这些研究将 阐明BE是否以及如何增强肥胖引起的神经炎症和神经变性 以及n-3多不饱和脂肪酸是否以及如何影响BE诱导的神经炎症和神经变性。这个 研究结果将改变关于BD和饮食介导的病理之间相互作用的范式 包括n-3多不饱和脂肪酸在预防阿尔茨海默病发病和进展中的特征。