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.

大量研究表明，神经炎症是阿尔茨海默病 (AD) 进展的关键因素。白细胞介素 (IL)-1β 是炎症的主要诱导剂，因此是治疗选择的主要目标。无活性的 IL-1β 前体需要由核苷酸结合寡聚化结构域样受体家族、含有热蛋白结构域 3 (NLRP3) 的炎性体加工成成熟且有活性的形式。研究表明，AD 患者大脑中 IL-1β 的表达上调，NLRP3 炎性体的基因失活可改善该疾病小鼠模型的行为测试和突触可塑性表型。在本研究中，我们分析了使用 dapansutrile (OLT1177) 对 NLRP3 炎症小体的药理抑制作用，dapansutrile (OLT1177) 是一种对人类安全的口服 NLRP3 特异性抑制剂。六个月大的 WT 和 APP/PS1 小鼠用标准小鼠饲料或富含 OLT1177 的饲料喂养 3 个月。Morris水迷宫测试显示9个月大的APP/PS1小鼠的学习和记忆能力受损（P = 0.001），而给小鼠喂食OLT1177可以完全挽救这种能力（对于未治疗的APP/PS1， P = 0.008）。此外，我们的研究结果表明，3 个月的 OLT1177 饮食可以挽救 AD 小鼠模型中的突触可塑性（与未经治疗的 APP/PS1 相比，P = 0.007）。此外，使用 OLT1177 抑制 NLRP3 后，小胶质细胞的激活程度较低（ P = 0.07），并且皮质中的斑块数量减少（P = 0.03）。我们还观察到 AD 血浆代谢标志物相对于 WT 小鼠的 OLT1177 剂量依赖性正常化。这项研究表明，口服 NLRP3 炎症小体抑制剂具有治疗神经炎症的潜力。