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

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the A<i>β</i>-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how A<i>β</i> mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric A<i>β</i> (o-A<i>β</i>) 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 <i>in vitro</i> (<i>si-Kv2.1</i>) and <i>in vivo</i> (AAV-ePHP-<i>si-Kv2.1</i>). Dfe deprived o-A<i>β</i> of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-<i>κ</i>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<i>β</i>-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.