Both Alzheimer's disease and heavy alcohol use cause dementia and their interaction on neuroinflammation, a key element in the pathogenesis of these conditions, is yet to be understood. We hypothesize that the Interferon Regulatory Factor 3 (IRF3) and the Stimulator of Interferon Genes (STING) signaling pathways are common and potentially synergistic in AD and alcohol-related neuroinflammation. IRF3 is a nuclear regulatory factor in Type I Interferon (IFN-I) induction and IFN-Is were recently shown to regulate neuroinflammation and neurodegeneration in AD. Because evaluation of AD dementia and neurodegeneration in mice models is based on behavioral assessments, we propose to build new resources in our laboratory for behavioral tests.
The Specific Aims of this study are: 1. To test the role of STING and IRF3 signaling pathways in alcohol- induced neuroinflammation and regulation of the expression of AD proteins by: a) Evaluating the effects of chronic alcohol feeding with and without binge on neuroinflammation in wild-type, IRF3-, STING- and cGAS- deficient mice on mRNA and protein expression of pro-inflammatory cytokine genes, inflammasome activation, IRF3 phosphorylation, IFN-I induction and microglia activation/polarization in the brain; b) Assessing the expression levels of AD-associated proteins in the cortex and hippocampus of wild type, IRF3-, STING- and cGAS-deficient mice after excessive alcohol intake with and without alcohol binge; c) Exploring the effects of chronic alcohol administration with and without alcohol binge on neuroinflammation, STING activation, IRF3 phosphorylation and IFN-I activation in AD transgenic mice (hAPPJ20) compared to WT mice; d) Testing effects of pharmacologic inhibition of IRF3 or STING on alcohol-induced neuroinflammation in wild-type mice.
Aim 2 is to establish resources and an infrastructure in our laboratory for a mouse behavioral phenotyping platform to test cognitive and social impairments associated with AD, including the Morris Water maze test for assessment of hippocampal-dependent spatial learning and memory formation, the novel object recognition test as an index of recognition memory, the open field test as a measure of anxiety and locomotor activity, and the resident intruder aggression task and three-chamber test to evaluate sociability. Experiments proposed in this supplement will explore novel signaling molecules in alcohol-induced neuroinflammation and interactions between alcohol use and key pathways in the biology of neuroinflammation and AD dementia. The proposed studies are within the scope of the parent grant and parallel investigation of the cGAS-STING-IFN-I pathways between alcohol-induced neuroinflammation and alcoholic liver disease will provide another unique insight into alcohol-induced organ damage. Our studies will reveal new potential therapeutic targets in the dual insult of alcohol use and Alzheimer's disease on the brain and dementias.
This research will examine the potential interactions between Alzheimer's disease and alcohol use by testing the role of key molecular pathways in inflammation in the brain. Brain inflammation contributes to development of dementias and our research aims to identify key molecules that can be targeted for future therapies.
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