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

翻译后摘要：肥胖已与神经炎症和神经退行性变。酗酒（BD） 据报道，也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许可的Inflamity Pathway Analysis（IPA）证实，乙醇（EtOH）和肥胖诱导 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AD。我们还进行了IPA分析 研究酒精和肥胖导致AD的途径酒精和肥胖都与酒精引起的AD有关 表现出AD发展的整体激活。这些研究还揭示了一个关键的知识差距， 过量乙醇（BE）增强肥胖诱导的神经炎症和神经变性。至关重要 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，多不饱和脂肪酸（PUFA）具有抗炎特性，对患有轻度认知障碍的老年人有有益作用。 损伤本实验室采用5周每周3天BE在周末模拟BD，发现 二十二碳六烯酸（DHA; 22：6 n-3），一种PUFA，改善BE诱导的HIV-1转基因大鼠炎症， 艾滋病病毒/艾滋病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 PUFAs可能会减少淀粉样前体蛋白（APP）的产生，APP是一种与细胞凋亡相关的关键分子。 AD的发病和进展。 把这些坚实的前提放在一起，我们假设BE可能会增加肥胖引起的 而n-3 PUFAs可以减轻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，我们将使用饮食诱导的肥胖症 通过给C57 BL/6 J小鼠喂食对照10 kcal%脂肪饮食（CD）、补充DHA的CD（DCD）、45% kcal%高脂饮食（HFD）、补充DHA的45 kcal%高脂饮食（DHFD），并提出两个目标。目标1： 检查BE对小鼠脑中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，喂食CD、DCD、HFD或DHFD（含或不含BE） 染色目的二是从分子水平研究BE对神经炎症和神经退行性变的影响。 使用RNA测序、抗体检测，用CD、DCD、HFD或DHFD（含或不含BE）喂养小鼠的脑中水平 阵列和生物信息学分析。 这些研究具有高度的临床意义。成功完成这些研究将 揭示BE是否以及如何增强肥胖诱导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。的 研究结果将改变关于BD和饮食介导的病理学之间相互作用的范式 包括表征n-3 PUFA在预防AD病理的发作和进展中的作用。

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.