CA-074 methyl ester, an inhibitor of cathepsin B, combined with the calcium channel blocker Nimodipine inhibits NLRP3 inflammasome activation and alleviates the lesions of Alzheimer's disease transgenic mice.

This study aims to investigate the effects of CA-074 methyl ester (CA-074Me) alone or in combination with Nimodipine on NLRP3 inflammasome activation; and evaluate therapeutic effects on transgenic mice of Alzheimer's disease (AD). APP/PS1 mice were fed with Cathepsin B inhibitor CA-074Me and Nimodipine, respectively. Morris water maze test was used to detect the changes in the learning and memory capacities of AD mice. ELISA was performed to detect IL-1β and IL-18 proteins. Immunohistochemistry was used to detect the NLRP3 and caspase-1 proteins. Immunoblotting was performed to detect NLRP3 in the brain tissue of mice in each group. Unlike the control group, the latency threshold of the CA-074Me group was significantly lower. In the space exploration experiment of mice, the time to find the platform in the CA-074Me group was significantly shorter than that in the control group, with a statistically significant difference. IL-1β in the CA-074Me group was significantly lower (t = 15.836, P < 0.001). Caspase-1 protein expression was significantly lower in the CA-074Me group than in the control group, with a statistically significant difference. As for the NLRP3 protein detected by immunoblotting, the (CA-074Me + Nimodipine) group was significantly lower than that in the control group; The relative expression of Aβ protein in CA-074Me group was significantly lower than that in the control group. In animal experiments on AD transgenic mice, CA-074Me alone or in combination with the calcium channel blocker Nimodipine effectively suppressed NLRP3 inflammasome activation, thereby inhibiting the progression of AD.