MicroRNAs in Alcoholic Liver Disease Administrative Supplement

Beth Israel Deaconess Medical Center, Boston MA

Investigators

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Abstract

ABSTRACT Both Alzheimer’s disease (AD) and alcohol-related dementia (ARD) are also rapidly increasing in the US. Both types of dementias exhibit memory loss and their pathomechanisms involve neuroinflammation and microglia activation Heavy alcohol use was can also increases the risk of AD. microRNA-155, a small non-coding RNA involved in regulation of inflammation, is upregulated in the brain in AD as well as in ARD. We showed that alcohol-induced neuroinflammation is attenuated in miR-155 deficient mice. Deletion of miR-155 also protected against memory deficits and neuroinflammation in a mouse model of AD. Based on these observations, we hypothesize that miR-155 upregulation in microglia plays a regulatory role in alcohol-induced as well as in AD neuroinflammation and memory deficits. We showed before that miR-155 also regulates the biogenesis of exosomes that are small extracellular vesicles (EVs) in macrophages. Here we will evaluate the role of miR-155 is in EV production in microglia. Further, we will assess miR-155 or other RNA components of EVs in AD and after alcohol exposure. Our hypotheses will be tested in the following Specific Aims: Aim#1 will evaluate the role of miR-155 on EV production and the EV cargo in vitro in microglia cultures by a) evaluating alcohol and Aβ-induced EV production in primary microglia from wild-type and miR-155 knockout mice; b) testing the effect miR-155 overexpression and knockdown on alcohol and amyloid beta (Aß)-induced EV production in BV2 cells; c) testing the effects of EVs derived from alcohol- or Aβ-stimulated microglia on activation of “naïve’ microglia. Aim#2 will investigate the role of miR-155 deletion on alcohol-induced memory deficits in C57/Bl6 (WT) and AD (5X FAD) mice in correlation with neuroinflammation and EV production by: a) assessing memory performance of mice in Morris Water Maze, b) enumerating EV levels from the brain tissue and characterizing the miRNA cargo of isolated EVs, c) evaluating the activation state of alcohol-induced microglia by transcriptomic profiling and neuroinflammation markers. Results from these experiments will provide novel insights into the role of miR-155 in alcohol-induced and AD-related memory loss, EV production and neuroinflammation.