NOTCH3 Mutation Causes Glymphatic Impairment and Promotes Brain Senescence in CADASIL

  • CNS Neurosci Ther. 2025 Jan;31(1):e70140. doi: 10.1111/cns.70140.
Chunyi Li  1  2 ,  Hui Li  1 ,  Xuejiao Men  1 ,  Yuge Wang  1 ,  Xinmei Kang  1 ,  Mengyan Hu  1 ,  Xiaotao Su  1 ,  Shisi Wang  1 ,  Danli Lu  1 ,  Shishi Shen  1 ,  Huipeng Huang  1 ,  Xiaohui Deng  1 ,  Yuxin Liu  1 ,  Lei Zhang  2 ,  Wei Cai  1  3 ,  Aimin Wu  1 ,  Zhengqi Lu  1
Affiliations
  • 1. Department of Neurology, Mental and Neurological Disease Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 2. Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.
  • 3. Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China.
PMID: 39853935 DOI: 10.1111/cns.70140
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 (Notch3R170C) 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; CADASIL; brain senescence; glymphatic system.
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