Brief intro:
- Author: Chunyi Li, Hui Li, Xuejiao Men, Yuge Wang, Xinmei Kang, Mengyan Hu, Xiaotao Su, Shisi Wang, Danli Lu, Shishi Shen, Huipeng Huang, Xiaohui Deng, Yuxin Liu, Lei Zhang, Wei Cai, Aimin Wu, Zhengqi Lu
- Journal: CNS Neuroscience & Therapeutics
- Publication Date: 2025 Jan 24
Abstract
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 R170C) 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.
Keywords: AQP4, brain senescence, CADASIL, glymphatic system
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