Alzheimer’s disease(AD)is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment.Synergistic effects of the Ab-Tau cascade reaction are tightly implicated in AD pathology,and microgli...Alzheimer’s disease(AD)is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment.Synergistic effects of the Ab-Tau cascade reaction are tightly implicated in AD pathology,and microglial NLRP3 inflammasome activation drives neuronal tauopathy.However,the underlying mechanism of how Ab mediates NLRP3 inflammasome remains unclear.Herein,we determined that oligomeric Ab(o-Ab)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-Ab of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-kB pathway while improving the cognitive impairment of 5FAD-AD model mice.Our results have highly addressed that the Kv2.1 channel is required for o-Ab-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.展开更多
基金supported by the National Natural Science Foundation for Young Scientists of China(82404629)the National Natural Science Foundation of China(82473982)+5 种基金the National Key R&D Program of China(2023YFC2308200)the Innovation Projects of State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture(NZYSKL240110,China)the Natural Science Foundation of Jiangsu Province(BK20240729,China)the Major Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(23KJA350002)the Jiangsu Province Science and Technology Project of Traditional Chinese Medicine(ZT202109,China)the Jiangsu Provincial Medical Innovation Center(CXZX202225,China)and the“Qing Lan”project.
文摘Alzheimer’s disease(AD)is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment.Synergistic effects of the Ab-Tau cascade reaction are tightly implicated in AD pathology,and microglial NLRP3 inflammasome activation drives neuronal tauopathy.However,the underlying mechanism of how Ab mediates NLRP3 inflammasome remains unclear.Herein,we determined that oligomeric Ab(o-Ab)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-Ab of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-kB pathway while improving the cognitive impairment of 5FAD-AD model mice.Our results have highly addressed that the Kv2.1 channel is required for o-Ab-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.
