O1‐08‐03: targeting nlrp3 inflammasome with a novel inhibitor for alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Recently, inflammasomes have been identified as intracellular multiprotein platforms that tightly regulate the innate immune response to pathogen-associated molecular patterns and danger-associated molecular patterns. Among known inflammasome families, NLRP3 inflammasome has been indicated a critical role in the pathogenesis of AD. We recently developed a novel small molecule inhibitor that selectively target the NLRP3 inflammasome. In this study, female APP/PS1 mice were treated with our novel compound JC124 for 2 months with oral gavage. After treatment, cognitive functions and AD pathologies, as well as protein expression levels of synaptic proteins were assessed. We found that our novel compound has shown therapeutic efficacy in a APP/PS1 mice. Specifically, treatment with our NLRP3 inhibitor JC124 significantly reduced multiple AD pathologies including A-beta load and neuroinflammation, enhanced synaptic plasticity with increased expression of pre- and post-synaptic proteins, as well as improved cognitive functions. Our study demonstrated that targeting NLRP3 infalmmasome formation is a viable therapy for AD.