The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

Abstract

Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer’s disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

“…As shown recently, cytokines up-regulate γ-secretase activity for Aβ production through expression of γ-secretase modulatory protein IFITM3 (interferon-induced transmembrane protein 3) in neurons and astrocytes [ 45 ]. Accordingly, blocking microglial inflammasome by the inhibitor dapansutrile (OLT1177) reduced microglia activity and cortical Aβ plaque deposition, and rescued cognitive function in AD mouse model [ 46 ]. In the early stage of AD, activated microglia cells remove cerebral Aβ deposits.…”

Curcuma Longa, the “Golden Spice” to Counteract Neuroinflammaging and Cognitive Decline—What Have We Learned and What Needs to Be Done

“…In vitro and in vivo studies have shown that Aβ peptide activates NLRP3 inflammasome in microglial cells. Furthermore, in a mouse model of AD, NLRP3 knockout (KO) mice were protected from impaired spatial memory performance and showed a decrease in the Aβ plaque load [ 67 ], similar results were obtained when a specific NLRP3 inhibitor was administered to mice [ 68 ]. This evidence points to the inflammasome as a potential therapeutic target for AD treatment [ 69 ].…”

Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases

“…Administration of OLT1177, an NLRP3 inflammasome inhibitor, rescued cognitive impairment and neuroinflammation in an APP/PS1 mouse model of Alzheimer’s disease (Lonnemann et al 2020 ). Activation of the NLRP3 inflammasome was increased in CRND8 APP transgenic mice, an Alzheimer's disease mouse model, compared to nontransgenic littermate controls, and treatment with JC-124, another NLRP3 inflammasome inhibitor, led to a decrease in amyloid-β deposition in the brain of CRND8 transgenic mice (Yin et al 2018 ).…”