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

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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.