NF-κB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related
Paige E Anton1,2, Prashant Nagpal3, Julie Moreno4
1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.
Abstract:
Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in aged adults is associated with neurodegeneration, yet the molecular underpinnings of 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-κB) 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 (18-20 months) female C57BL/6N mice compared to young (3-4 months). In primary microglia, ethanol-induced expression of reactivity markers and NLRP3 inflammasome activation were more pronounced in microglia from aged mice compared to young. Making use of an NLRP3-specific inhibitor (OLT1177) and a novel brain-penetrant Nanoligomer that inhibits NF-κB 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-1β 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 NF-κB- and NLRP3-dependent. Further investigation is warranted to explore the use of targeted immunosuppression via Nanoligomers to attenuate neuroinflammation after alcohol consumption in the aged.
Insights
Binge alcohol use elevates NLRP3 inflammasome activation in aged mice microglia, contributing to neuroinflammation. Inhibiting NF-κB and NLRP3 with Nanoligomers may protect the aging brain from alcohol-induced damage.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Binge alcohol consumption is rising in older adults, increasing neurodegeneration risk.
- Molecular mechanisms of alcohol sensitivity in aging brains remain unclear.
- NF-κB and NLRP3 pathways drive microglia activation and neuronal injury in neurodegenerative models.
Approach:
- Compared microglia activation in young and aged mice after binge ethanol exposure.
- Utilized NLRP3 inhibitor (OLT1177) and a novel NF-κB/NLRP3 inhibitor (SB_NI_112).
- Assessed microglial reactivity, IL-1β production, and tau hyperphosphorylation in aged mice models.
Key Points:
- Aged mice showed increased NLRP3+ microglia in the hippocampus post-binge ethanol.
- Ethanol induced greater microglial reactivity and NLRP3 activation in aged primary microglia.
- OLT1177 and SB_NI_112 attenuated ethanol-induced microglial reactivity in aged microglia.
- SB_NI_112 prevented ethanol-mediated neuroinflammation and tau hyperphosphorylation in aged mice.
Conclusions:
- NF-κB and NLRP3 pathways are implicated in age-related brain changes due to binge alcohol.
- Targeted immunosuppression using Nanoligomers shows potential for mitigating alcohol-induced neuroinflammation in the elderly.
- Further research is needed to explore Nanoligomer efficacy in aged populations.
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