Regulatory effect of BTK on mouse Alzheimer disease-like pathology via NEK7-NLRP3 signaling pathway
10.3969/j.issn.1000-4718.2024.09.001
- VernacularTitle:BTK通过NEK7-NLRP3信号通路对小鼠阿尔茨海默样病变的调控作用
- Author:
Jianfeng MA
1
;
Xiaobing LI
;
Qiying SHEN
;
Mei CHEN
;
Qiuyu XIE
;
Yinghua LIU
Author Information
1. 广州医科大学药学院药理学教研室,广州分子与临床药理研究所,国家药品监督管理局胸腔疾病药物临床研究与评价重点实验室,广东省分子靶标与临床药理学重点实验室,广东 广州 511436
- Keywords:
Alzheimer disease;
Bruton tyrosine kinase;
NEK7/NLRP3 signaling pathway;
Neuroinflammation
- From:
Chinese Journal of Pathophysiology
2024;40(9):1569-1579
- CountryChina
- Language:Chinese
-
Abstract:
AIM:To investigate the impact of Bruton tyrosine kinase(BTK)on Alzheimer disease(AD)-like pathology through the NIMA(never in mitosis gene A)-related kinase 7(NEK7)-nucleotide-binding oligomerization do-main-like receptor protein 3(NLRP3)pathway.METHODS:5xFAD and wild-type(WT)mice aged 2,4 and 6 months were utilized to assess the expression of BTK,NEK7 and NLRP3 proteins in the hippocampus and cortex via Western blot and immunofluorescence.Co-immunofluorescence was conducted to identify the interaction between NEK7 and NLRP3 in the brains of 4-month-old mice.Three-month-old mice were divided into a control group and an ibrutinib treatment group,receiving intraperitoneal injections of ibrutinib(10 mg/kg)or solvent for 14 d,and were then subjected to behavioral as-sessments including learning and memory tests using the Morris water maze and Y-maze.Wild-type mice were induced with an AD model by intracerebroventricular injection of Aβ42.Morris water maze tests were performed after 14 d to eva-luate learning and memory,followed by measurement of BTK protein levels in the brain via Western blot.BV2 microglial cells were treated with ibrutinib,followed by LPS or Aβ42 stimulation.Western blot analysis was conducted to measure the protein levels of NEK7,NLRP3,BTK and p-BTK(Y223),while immunofluorescence was used to assess the protein expression of ASC,caspase-1,NEK7 and NLRP3.RESULTS:The levels of BTK,NEK7 and NLRP3 in the brains of 5×FAD mice were significantly elevated compared to WT mice,with observed interaction between NEK7 and NLRP3 in the 5xFAD mouse brains.Ibrutinib treatment significantly improved learning and memory functions in mice compared to the AD group.In BV2 cells,pre-treatment with ibrutinib effectively suppressed the NLRP3 inflammasome pathway and NEK7 proteins in response to Aβ42 stimulation.CONCLUSION:BTK plays a regulatory role in AD-like pathology through the NEK7-NLRP3 pathway both in vivo and in vitro.
