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

基本信息

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
项目类别：
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

项目摘要

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。酗酒（BD）据报道，它还会导致神经炎症和脑萎缩。此外，我们的生物信息学分析使用 QIAGEN 授权的 Ingenuity Pathway Analysis (IPA) 证实乙醇 (EtOH) 和肥胖会诱发神经炎症。研究表明酒精和肥胖以神经炎症和神经变性为中心环节的疾病（AD）。我们还进行了 IPA 分析研究从酒精和肥胖到 AD 的路径。酒精和肥胖都与酒精相关的AD有关表现出AD发展的全面激活。这些研究还揭示了一个关键的知识差距暴食乙醇（BE）会加剧肥胖引起的神经炎症和神经变性。作为必要的神经元和神经胶质细胞膜的营养素和基本成分、n-3 多不饱和脂肪酸据报道，PUFA（多不饱和脂肪酸）具有抗炎特性，并对患有轻度认知障碍的老年人有有益作用损害。我们的实验室使用每周 3 天、5 周的 BE 来模拟周末的 BD，结果发现二十二碳六烯酸 (DHA; 22:6n-3) 是一种 PUFA，可改善 HIV-1 转基因大鼠中 BE 诱导的炎症，接受联合抗逆转录病毒治疗的艾滋病毒/艾滋病患者的动物模型。使用 IPA，我们发现 n-3 PUFA 可能会减少淀粉样前体蛋白 (APP) 的产生，APP 是与淀粉样蛋白相关的关键分子 AD 的发病和进展。综合考虑这些坚实的前提，我们假设 BE 可能会加剧肥胖引起的神经炎症和神经变性，而 n-3 PUFA 可以减轻 BE 诱导的神经炎症和神经变性。为了检验这些假设，我们将使用饮食诱发的肥胖通过用对照 10 kcal% 脂肪饮食 (CD)、添加 DHA 的 CD (DCD)、45% 喂养 C57BL/6J 小鼠来建立小鼠模型 kcal%高脂肪饮食（HFD）、添加DHA的45 kcal%高脂肪饮食（DHFD）并提出两个目标。目标 1 是检查 BE 对小鼠大脑细胞水平的神经炎症和神经变性的影响使用免疫荧光染色和 Fluoro-Jade B 饲喂 CD、DCD、HFD 或 DHFD，有或没有 BE 染色。目标 2 是从分子水平研究 BE 对神经炎症和神经变性的影响使用 RNA 测序、抗体检测喂食 CD、DCD、HFD 或 DHFD 且有或没有 BE 的小鼠大脑中的水平阵列和生物信息分析。这些研究具有非常重要的临床意义。成功完成这些研究将揭示 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 PUFA 是否以及如何影响 BE 诱导的神经炎症和神经变性。这研究结果将改变双相情感障碍与饮食介导的病理之间相互作用的范式包括 n-3 PUFA 在预防 AD 病理的发生和进展方面的特性。