Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis

作者：Jian Lu, Qian Zhou, Danyang Zhu, Hongkuan Song, Guojia Xie, Xuejian Zhao, Yujie Huang, Peng Cao, Jiaying Wang, Xu Shen · 发表于：Acta Pharmaceutica Sinica B · 年份：2024 · DOI：10.1016/j.apsb.2024.11.010 · 被引用次数：5 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Signaling Pathways in Disease、Adenosine and Purinergic Signaling

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the A β -Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how A β mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric A β (o-A β ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro ( si-Kv2.1 ) and in vivo (AAV-ePHP- si-Kv2.1 ). Dfe deprived o-A β of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF- κ B pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-A β -driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD. Kv2.1 inhibitor Dfe effectively suppressed o-A β -induced microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF- κ B pathway, while improving the cognitive impairment of 5×FAD-AD mice.