NOTCH3突变导致CADASIL患者的类淋巴系统损伤并促进脑衰老。

NOTCH3 Mutation Causes Glymphatic Impairment and Promotes Brain Senescence in CADASIL.

作者信息

Li Chunyi, Li Hui, Men Xuejiao, Wang Yuge, Kang Xinmei, Hu Mengyan, Su Xiaotao, Wang Shisi, Lu Danli, Shen Shishi, Huang Huipeng, Deng Xiaohui, Liu Yuxin, Zhang Lei, Cai Wei, Wu Aimin, Lu Zhengqi

机构信息

Department of Neurology, Mental and Neurological Disease Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.

出版信息

CNS Neurosci Ther. 2025 Jan;31(1):e70140. doi: 10.1111/cns.70140.

DOI:10.1111/cns.70140

PMID:39853935

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11760990/

Abstract

AIMS

The aim of this study is to investigate the role of glymphatic function of cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL), the most common monogenic small vessel disease caused by NOTCH3 mutation, and to explore potential therapeutic strategies to improve glymphatic function.

METHODS

We assessed glymphatic influx and efflux function in CADASIL mouse models (Notch3) and correlated these findings with brain atrophy in CADASIL patients. We also investigated the underlying mechanisms of glymphatic impairment, focusing the expression of AQP4 in astrocytic endfeet.

RESULTS

CADASIL mouse exhibited both impaired glymphatic influx and efflux, which impedes waste clearance and promotes brain senescence. In accordance, brain atrophy in CADASIL patients is associated with perivascular space enlargement, indicating that glymphatic impairment contributes to advanced brain senescence in CADASIL. The glymphatic malfunction in CADASIL is attributed to diminished AQP4 expression in astrocytic endfeet, which is the core mediator of glymphatic activity. Mechanistically, AQP4 expression is regulated by NOTCH3-RUNX1-CMYB signaling. Reinforcing AQP4 expression in astrocytes by AAV-based therapy resumes the glymphatic functions in CADASIL mice, which further prevents brain senescence.

CONCLUSION

We propose that to improve glymphatic function by reinforcing AQP4 expression is a promising therapeutic strategy in CADASIL.

摘要

目的

本研究旨在探讨大脑常染色体显性动脉病伴皮质下梗死和白质脑病（CADASIL）中淋巴系统功能的作用，CADASIL是由NOTCH3突变引起的最常见的单基因小血管疾病，并探索改善淋巴系统功能的潜在治疗策略。

方法

我们评估了CADASIL小鼠模型（Notch3）中的淋巴系统流入和流出功能，并将这些结果与CADASIL患者的脑萎缩情况相关联。我们还研究了淋巴系统受损的潜在机制，重点关注星形胶质细胞终足中水通道蛋白4（AQP4）的表达。

结果

CADASIL小鼠表现出淋巴系统流入和流出均受损，这阻碍了废物清除并促进了脑衰老。相应地，CADASIL患者的脑萎缩与血管周围间隙扩大有关，表明淋巴系统受损促成了CADASIL中晚期脑衰老。CADASIL中的淋巴系统功能障碍归因于星形胶质细胞终足中AQP4表达减少，而AQP4是淋巴系统活动的核心介质。从机制上讲，AQP4表达受NOTCH3-RUNX1-CMYB信号通路调控。通过基于腺相关病毒（AAV）的疗法增强星形胶质细胞中的AQP4表达可恢复CADASIL小鼠的淋巴系统功能，进而预防脑衰老。