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

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.

Grant Number: 1R21AA030221-01A1
NIH Institute/Center: NIH
Principal Investigator: Sulie Chang