Neuroinflammatory GeroMiRs and Alcohol: Defining Mechanisms of ADRD

Project Summary The proposed project will examine the mechanisms by which ethanol-related dementia is greater in older subjects. We live in a rapidly aging society which as been designed the “Silver Tsunami” of individuals aged 65 or older (i.e. advanced age, aged). Accordingly, the number of chronic diseases, including age-related dementia,

is increasing and 90% of dementia cases are sporadic and driven by environmental cues. Approximately forty percent of aged adults consume alcohol and the prevalence of binge drinking in older adults is on the rise. Despite these trends, there are significant gaps in knowledge related to the health impacts of alcohol use and

misuse in individuals with advanced age; this proposal aims to fill these gaps in knowledge. Chronic inflammation is a critical driving factor of neurodegeneration and cognitive decline and is independently increased by both age and alcohol. We and others hypothesize that heightened inflammatory responses predisposing older individuals

to alcohol-induced end organ damage is at least partly attributed to the effects of low-grade chronic inflammation that increases with age, termed "inflamm-aging." Because both inflamm-aging and alcohol independently and negatively impact the resident macrophages in the brain, the microglia, is our working hypothesis that relative to

young, older subjects have heightened inflammatory responses that fail to resolve, leading to excessive systemic and neuroinflammation and damage to critical organs like the brain. Accordingly, the associated hippocampal damage will drive accelerated cognitive decline and early onset dementia. In this proposal, we will explore how

age and alcohol impact the expression of regulatory miRNAs in microglia, and determine if these changes result as 1) a direct effect of ethanol toxicity and 2) an indirect effect via the gut-brain axis. To investigate the role of alcohol and age on neuroinflammatory responses, in Aim1 we will make use of a novel mouse model of binge

ethanol exposure to establish the neurotoxic effects of alcohol on disease progression and early onset dementia in aged mice. We will also make use of primary microglia from young and aged mice and profile the microRNA/mRNA landscape in response to in vivo ethanol exposure. In Aim 2, we will examine the role of

miR223 as an important regulatory factor modulating inflammatory responses in microglia and will establish if gene therapy replacement of miR223 will prevent ethanol-induced neuroinflammation and dementia in aged

mice. Finally, Aim 3 will focus on the gut-brain axis and will be able, for the first time, to monitor age-related shifts in the microbiome and determine if age-related intestinal dysbiosis can predispose neuroinflammatory responses to alcohol, via elevated systemic inflammation and changes to regulatory miRNAs in microglia. These studies

will expand our understanding of how components of “inflamm-aging” lead to dysregulated miRNA profiles in immunomodulatory components in the brain, which are critical sensitizing factors during bouts of ethanol exposure and withdrawal. Importantly, this work may highlight/discover novel targets leading to the development

of therapeutic strategies to improve or prevent early onset dementia in patients of all ages.