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; 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变性有关。暴饮暴食（BD） 据报道，还导致神经炎症和脑萎缩。而且，我们的生物信息学分析 使用Qiagen许可的Ingenuity途径分析（IPA）证实乙醇（ETOH）和肥胖症诱导 神经炎症。研究表明酒精和肥胖症 具有神经炎症和神经退行性的疾病（AD）作为中心联系。我们还进行了IPA分析 检查从酒精和肥胖到AD的路径。酒精和肥胖都与酒精有关 表现出广告开发的总体激活。这些研究还揭示了有关的关键知识差距 肥胖诱导的神经炎症和神经变性的狂热ETOH（BE）增强。至关重要 神经元和神经胶质细胞膜的营养和基本成分，N-3多不饱和脂肪酸 （PUFAS）据报道具有抗炎特性和对老年人的有益作用 损害。我们的实验室每周使用5周的3天，是在周末模仿BD，发现 Docosahexaenoic Acid（DHA; 22：6n-3），PUFA，可以改善HIV-1转基因大鼠的炎症，炎症， HIV/AIDS患者的动物模型进行抗逆转录病毒疗法。使用IPA，我们发现N-3 PUFA可能会降低淀粉样蛋白前体蛋白（APP）的产生，这是一种与之相关的关键分子 AD的发作和进展。 我们假设将这些坚实的前提放在一起，可能会增加肥胖引起的 神经炎症和神经变性，而N-3 PUFA可能会诱导 神经炎症和神经变性。为了检验这些假设，我们将使用饮食引起的肥胖 通过对照10 kcal％脂肪饮食（CD）喂食C57BL/6J小鼠的小鼠模型，DHA补充CD（DCD），45％ KCAL％高脂肪饮食（HFD），DHA供电的45 kcal％高脂肪饮食（DHFD），并提出了两个目标。目标1是 检查BE对小鼠大脑细胞水平上神经炎症和神经退行性的影响 用CD，DCD，HFD或DHFD喂食或不使用免疫荧光染色和氟jade B 染色。 AIM 2是检查BE对分子神经炎症和神经退行性的影响 用CD，DCD，HFD或DHFD喂养的小鼠的大脑中的水平，或者不使用RNA序列，抗体 阵列和生物信息学分析。 这些研究具有临床相关性非常重要。这些研究的成功完成将 揭示是否以及如何增加肥胖引起的神经炎症和神经变性 以及n-3 PUFA是否可能影响神经炎症和神经变性。这 研究结果应改变有关BD和饮食介导的病理之间相互作用的范式 包括对N-3 PUFA的表征，以防止AD病理的发作和进展。