Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder. Neuroinflammation has been recognized as an essential player in the development of AD, especially for the late-onset AD. This notion is supported by the facts that microglial activation, reactive astrocytes along with elevated cytokines have been observed in AD models and patients. Furthermore, epidemiological studies have demonstrated that long-term use of non-steroidal anti-inflammatory drugs can prevent or delay the onset of AD. Inflammasomes have been recently identified as multiprotein complexes that tightly regulate the innate immune response and the production of pro-inflammatory cytokines. Among the known inflammasomes, NLRP3 inflammasome is the most extensively studied and widely implicated regulator of caspase-1 activation, the maturation and production of IL-1β and IL-18. Notably, numerous recent studies have indicated a critical role for NLRP3 inflammasome and IL-1β in the pathogenesis of AD. Therefore, it would be of significant importance to develop novel NLRP3 inflammasome inhibitors to help further unravel the roles of NLRP3 inflammasome in the pathogenesis of AD. Recently, our lab has identified a novel NLRP3 inflammasome inhibitor. Biological characterization demonstrated that this inhibitor is selective to NLRP3 inflammasome, reduces the production of IL-1beta and IL-18. More importantly, it reduces inflammatory responses and improves cognitive functions in a TBI model, thus demonstrating its CNS activities. In this application, two aims are proposed. Aim 1 is to test the effects of this lead inhibitor on the pathological and cognitive functions in a transgenic AD mouse model. Preliminary DMPK studies will also be conducted to guide further development. Aim 2 is to structurally optimize this lead inhibitor to develop more potent analogs for further development as AD-modifying agents. The proposed research is innovative and our compelling preliminary results indicate that this strategy is promising and could lead to a new direction in development of effective AD treatments.