Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis.
10.1016/j.apsb.2024.11.010
- Author:
Jian LU
1
;
Qian ZHOU
2
;
Danyang ZHU
3
;
Hongkuan SONG
1
;
Guojia XIE
1
;
Xuejian ZHAO
1
;
Yujie HUANG
1
;
Peng CAO
2
;
Jiaying WANG
1
;
Xu SHEN
1
Author Information
1. School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
2. Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
3. School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
- Publication Type:Journal Article
- Keywords:
Alzheimer's disease;
Aβ-Tau cascade reaction;
Cognitive impairment;
Drofenine;
Kv2.1 channel;
Microglia;
NLRP3 inflammasome;
Potassium efflux
- From:
Acta Pharmaceutica Sinica B
2025;15(1):371-391
- CountryChina
- Language:English
-
Abstract:
Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) 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-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB 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-Aβ-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.
