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Alcohol-related toxicity in aged adults is associated with neurodegeneration; yet, the molecular underpinnings of this age-related sensitivity to alcohol are not well described. Studies utilizing rodent models of neurodegenerative disease reveal heightened activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) and Nod-like receptor 3 (NLRP3) mediate microglia activation and associated neuronal injury. Our group, and others, have implicated hippocampal-resident microglia as key producers of inflammatory mediators; yet, the link between inflammation and neurodegeneration has not been established in models of binge ethanol exposure and advanced age. Here, we report binge ethanol increased the proportion of NLRP3+ microglia in the hippocampus of aged (18 to 20\u2005mo) female C57BL\/6N mice compared with young (3 to\u20054 mo). In primary microglia, ethanol-induced expression of reactivity markers and NLRP3 inflammasome activation were more pronounced in microglia from aged mice compared with young. Using a NLRP3-specific inhibitor (OLT1177) and a novel brain-penetrant Nanoligomer that inhibits NF-\u03baB and NLRP3 translation (SB_NI_112), we find ethanol-induced microglial reactivity can be attenuated by OLT1177 and SB_NI_112 in microglia from aged mice. In a model of intermittent binge ethanol exposure, SB_NI_112 prevented ethanol-mediated microglia reactivity, IL-1\u03b2 production, and tau hyperphosphorylation in the hippocampus of aged mice. These data suggest early indicators of neurodegeneration occurring with advanced age and binge ethanol exposure are driven by NF-\u03baB and NLRP3. Further investigation is warranted to explore the use of targeted immunosuppression via Nanoligomers to attenuate neuroinflammation after alcohol consumption in the aging populations.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf024","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T23:19:55Z","timestamp":1740525595000},"source":"Crossref","is-referenced-by-count":6,"title":["Suppression of NF-\u03baB\/NLRP3 by nanoligomer therapy mitigates ethanol and advanced age-related neuroinflammation"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6720-7098","authenticated-orcid":false,"given":"Paige E","family":"Anton","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"Alcohol Research Program, School of Medicine, University of Colorado Anschutz 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CO 80523, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A","family":"Burchill","sequence":"additional","affiliation":[{"name":"GI and Liver Innate Immune Program, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anushree","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Sachi Bioworks Inc. , Louisville, CO 80516, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Busquet","sequence":"additional","affiliation":[{"name":"Animal Behavior & In Vivo Neurophysiology Core, NeuroTechnology Center, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"Department of Neurology, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mesches","sequence":"additional","affiliation":[{"name":"Animal Behavior & In Vivo Neurophysiology Core, NeuroTechnology Center, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"Department of Neurology, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Alcohol Research Program, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"Division of GI Trauma and Endocrine Surgery, Department of Surgery, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"Veterans' Health Administration, Eastern Colorado Health Care System, Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC) , Aurora, CO 80045, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5341-7326","authenticated-orcid":false,"given":"Rebecca L","family":"McCullough","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"Alcohol Research Program, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United States"},{"name":"GI and Liver Innate Immune Program, School of Medicine, University of Colorado Anschutz Medical Campus , Aurora, CO 80045, United 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