Targeting connexin hemichannels and the inflammasome response in an acute mouse model of Alzheimer’s disease

Pathologically activated connexin hemichannels can establish a self-propagating inflammasome activation loop that may contribute to Alzheimer’s disease (AD). This study aims to investigate the potential of modulating the inflammasome loop through connexin hemichannel blockade in a mouse model of AD known to display neurodegeneration, neuroinflammation, and memory deficits. One day after intrahippocampal injection of aggregated amyloid beta 1-42 (AB1-42), treatment mice (n=8) were administered a connexin hemichannel blocker, Tonabersat, in a peanut butter pellet for 16 days before tissue collection. AB1-42 injected mice (n=8) were given a peanut butter only, while Naïve controls (n=8) received no pellet. Fluorescent immunohistochemistry and densitometry analysis were used to quantify activation of astrocytes, microglia, the NLRP3 inflammasome, and Cleaved-Caspase 1 in the hippocampus. Preliminary results show significant increases in the astrocyte marker Glial Fibrillary Acidic Protein (GFAP) and the pro-inflammatory cytokine cleaved-caspase 1 (CC1) density in the hippocampus of AB1-42 injected mice compared to Naïve controls (*p=0.04 and *p=0.01, respectively). Treatment with a connexin hemichannel blocker brings GFAP and CC1 back down to Naïve levels, showing no difference between these groups (p=0.99 and p=0.29, respectively). Based on qualitative observations, the NLRP3 inflammasome and microglia appear to be highly present in areas of astrogliosis in the hippocampus of AB1-42 injected mice. These results suggest targeting connexin hemichannels may reduce the inflammatory response and limit inflammasome-associated consequences of AB1-42. This research highlights a potential therapeutic for AD to break the hostile inflammasome loop triggered by AB1-42.