O2‐13‐06: Development of NLRP3 Inflammasome Inhibitors for Alzheimer's Disease

Abstract

for 21 overlapping inflammatory markers ( Figure 1C shows results for IP-10), although ceiling effects may limit MSD for some markers ( Figure 1D). We analyzed the association of these and other markers with the ratio of CSF total-tau (t-tau) to Ab 42 , a widely used index of disease progression. Even in this limited sample, we observed significant correlation (p <0.05) between IL-1b, IL-8, IP-10, MCP-1, or TNF-a (all measurable using both platforms) and log t-tau/Ab 42 (e.g., Figure 1A, 1B). MCP-4 and TARC were also correlated with log t-tau/Ab 42 , but were measurable by MSD only. Conclusions: Changes in markers of AD progression may be used in high-risk populations to assess potential of candidate preventive interventions. The importance of inflammatory processes in AD pathogenesis is suggested by a strong association between several inflammatory markers and an established index of AD progression. Our results suggest a rationale for testing anti-inflammatory treatments as potential preventives that may delay onset of AD symptoms -now under investigation in INTREPAD. The longitudinal pattern of individual inflammatory markers and their response to NSAID treatment may reveal much about the etio-pathogenesis of AD.Background:Inflammasomes have been indicated a critical role in the pathogenesis of Alzheimer's disease (AD). Small molecule NLRP3 inflammasome inhibitors were developed as potential therapeutic agents for AD. Methods: Small molecule NLRP3 inflammasome inhibitors were designed and synthesized. J774A.1 cells were treated with compounds and the levels of IL-1beta were analyzed. APP/ PS1 mice were treated with compound for three months and pathology and behavioral functions were analyzed. Results: Compound GA3 selectively inhibited NLRP3 inflammasome, not other inflammasomes such as AIM2 and NLRC4. In addition, GA3 specifically targeted the NLRP3 inflammasome complex to exhibit the observed effects on the level of IL-1beta. In APP/PS1 mice, treatment with GA3 significntly suppressed microglia activation and inflammation as reflected by the reduced expression levels of inflammatory markers ED1 and OX6. Furthermore, treatment with GA3 significantly reduced the Abeta burden and improved the behaviroal functions in Morris water maze latency and probe trial tests. APP/PS1 mice also demonstrated improved performance in novel object recognition test and fear conditioning test after GA3 treatment. Conclusions: Selective NLRP3 inflammasome inhibitors have been successfully developed and treatment of APP/PS1 mice with our inhibitor significantly reduced AD pathologies and improved performance in multiple behaviroal tests, suggesting that targeting NLRP3 inflammasome could be a effective strategy to develop novel therapeutics for AD.Background: Antipsychotic medications continue to be prescribed for the management of Behavioral and Psychological Symptoms of Dementia (BPSD) despite revised guidelines, tighter regulation and evidence for the associated risks including accelerated cognitive decline, stroke and death. Th...