Inhibition of CXXC5 function rescues Alzheimer's disease phenotypes by restoring Wnt/β-catenin signaling pathway

被引：6

作者：

Yoon, Minguen ^{[1
]}

Kim, Heejene ^{[1
]}

Shin, Heewon ^{[2
]}

Lee, Heeyang ^{[2
]}

Kang, Min-Jeong ^{[4
]}

Park, Sung-Hye ^{[3
]}

Han, Gyoonhee ^{[1
]}

Kim, Youngsoo ^{[2
]}

Choi, Kang-Yell ^{[1
,4
]}

机构：

[1] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 03722, South Korea

[2] Yonsei Univ, Yonsei Inst Pharmaceut Sci, Coll Pharm, Dept Pharm, Incheon 21983, South Korea

[3] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 03080, South Korea

[4] CK Regeon Inc, Seoul 03722, South Korea

来源：

PHARMACOLOGICAL RESEARCH | 2023年 / 194卷

基金：

新加坡国家研究基金会;

关键词：

Alzheimer's disease; 5xFAD; Wnt/beta-catenin signaling pathway; CXXC5; Cxxc5(-/-)/5xFAD mice; CXXC5-Dvl protein-protein interaction; TRANSCRIPTION; ACTIVATION; HYPOTHESIS; PLAQUES; MICE;

D O I：

10.1016/j.phrs.2023.106836

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Alzheimer's disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenesis in AD. Increasing evidence suggests that the suppression of the Wnt/beta-catenin signaling pathway plays substantial roles in AD progression. However, the underlying mechanism for the suppression of Wnt/beta-catenin pathway associated with AD pathogenesis remains unexplored. In this study, we identified that CXXC5, a negative feedback regulator of the Wnt/beta-catenin pathway, was overexpressed in the tissues of AD patients and 5xFAD transgenic mice paired with the suppression of Wnt/beta-catenin pathway and its target genes related to AD. The level of CXXC5 was upregulated, upon aging of 5xFAD mice. AD characteristics including cognitive deficits, amyloid-beta (A beta) plaques, neuronal inflammation, and age-dependent increment of AD-related markers were rescued in Cxxc5(-/-)/5xFAD mice. 5methoxyindirubin-3'-oxime (KY19334), a small molecule that restores the suppressed Wnt/beta-catenin pathway via interference of the CXXC5-Dvl interaction, significantly improved the overall pathogenic phenotypes of 5xFAD mice. Collectively, our findings revealed that CXXC5 plays a key role in AD pathogenesis and suggest inhibition of CXXC5-Dvl interaction as a new therapeutic approach for AD.

引用

页数：12