NF-kB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation

Anton, P. E.; Nagpal, P.; Moreno, J.; Busquet, N.; Burchill, M. A.; Chatterjee, A.; Mesches, M.; Kovacs, E. J.; McCullough, R. L.

doi:10.1101/2024.02.26.582114

bioRxiv · 10.1101/2024.02.26.582114

NF-kB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation

Anton, P. E.·Nagpal, P.·Moreno, J.·Busquet, N.·Burchill, M. A.·Chatterjee, A.·Mesches, M.·Kovacs, E. J.·McCullough, R. L.

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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-{kappa}B) 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-{kappa}B 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{beta} 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-{kappa}B- 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.

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Anton, P. E., Nagpal, P., Moreno, J., Busquet, N., Burchill, M. A., Chatterjee, A., Mesches, M., Kovacs, E. J., McCullough, R. L.. 2024-02-28. NF-kB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation. https://doi.org/10.1101/2024.02.26.582114

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