The activation of the NLRP3 inflammasome signaling pathway plays an important role in the neuroinflammation in Alzheimer’s disease (AD). In this study, we investigated the effects of JC-124, a rationally designed NLRP3 inflammasome inhibitor, on AD-related deficits in CRND8 APP transgenic mice (TgCRND8). We first demonstrated increased formation and activation of NLRP3 inflammasome in TgCRND8 mice compared to non-transgenic littermate controls, which was inhibited by the treatment with JC-124. Importantly, JC-124 treatment led to decreased levels of Aβ deposition and decreased levels of soluble and insoluble Aβ1–42 in the brain of CRND8 mice which was accompanied by reduced β-cleavage of APP, reduced activation of microglia but enhanced astrocytosis. Oxidative stress was decreased and synaptophysin was increased in the CRND8 mice after JC-124 treatment, demonstrating a neuroprotective effect. Overall, these data demonstrated beneficial effects of JC-124 as a specific NLRP3 inflammasome inhibitor in AD mouse model and supported the further development of NLRP3 inflammasome inhibitors as a viable option for AD therapeutics.

NLRP3 inflammasome plays critical roles in a variety of human diseases and represents a promising drug target. In this study, we established the in vivo functional activities of JC124, a previously identified NLRP3 inflammasome inhibitor from our group, in mouse models of Alzheimer's disease and acute myocardial infarction. To understand the chemical space of this lead structure, a series of analogues were designed, synthesized, and biologically characterized. The results revealed the critical roles of the two substituents on the benzamide moiety of JC124. On the other hand, modifications on the sulfonamide moiety of JC124 are well tolerated. Two new lead compounds, 14 and 17, were identified with improved inhibitory potency (IC values of 0.55 ± 0.091 and 0.42 ± 0.080 μM, respectively). Further characterization confirmed their selectivity and in vivo target engagement. Collectively, the results strongly encourage further development of more potent analogues based on this chemical scaffold.

In our efforts to develop novel small-molecule inhibitors for the NOD-like receptor family pyrin-domain-containing 3 (NLRP3) inflammasome as potential disease-modifying agents to treat neurological disorders including multiple sclerosis (MS), a hydroxyl sulfonamide analogue JC-171 has been rationally designed and biologically characterized both in vitro and in vivo. Our studies established that JC-171 dose dependently inhibited LPS/ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC50 of 8.45 ± 1.56 μM. Selective inhibition of the NLRP3 inflammasome induced IL-1β release by this compound was also confirmed using mouse bone-marrow-derived macrophages and LPS-challenged mice in vivo. Furthermore, immunoprecipitation study revealed that JC-171 interfered with NLRP3/ASC interaction induced by LPS/ATP stimulation. More importantly, JC-171 treatment delayed the progression and reduced the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, in both prophylactic and therapeutic settings. This coincided with blocking of IL-1β production and a pathogenic Th17 response. Collectively, these results suggest that JC-171 is a selective NLRP3 inflammasome inhibitor with biological activity in vivo, thus strongly encouraging further development of this lead compound as a potential therapeutic agent for human MS.

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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...