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

被引：1

作者：

Lu, Jian ^{[1
]}

Zhou, Qian ^{[2
]}

Zhu, Danyang ^{[3
]}

Song, Hongkuan ^{[1
]}

Xie, Guojia ^{[1
]}

Zhao, Xuejian ^{[1
]}

Huang, Yujie ^{[1
]}

Cao, Peng ^{[2
,4
]}

Wang, Jiaying ^{[1
]}

Shen, Xu ^{[1
,4
]}

机构：

[1] Nanjing Univ Chinese Med, Sch Med, Nanjing 210023, Peoples R China

[2] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Wester, Jiangsu Prov Med Innovat Ctr, Nanjing 210028, Peoples R China

[3] Nanjing Univ Chinese Med, Sch Integrat Med, Nanjing 210023, Peoples R China

[4] Nanjing Univ Chinese Med, State Key Lab Technol Chinese Med Pharmaceut Proc, Nanjing 210023, Peoples R China

来源：

ACTA PHARMACEUTICA SINICA B | 2025年 / 15卷 / 01期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

Alzheimer's disease; A/3-Tau cascade reaction; Microglia; NLRP3; inflammasome; Kv2.1; channel; Potassium efflux; Drofenine; Cognitive impairment; INDUCED APOPTOSIS; ACTIVATION; MODULATION; OLIGOMERS; STRESS; CELLS;

D O I：

10.1016/j.apsb.2024.11.010

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the A/3-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how A/3 mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric A/3 (o-A/3) 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/3 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 5 xFAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-A/3-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.

引用

页码：371 / 391

页数：21

共 55 条

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