ArticleCNS neuroscience & therapeutics2025
NOTCH3 Mutation Causes Glymphatic Impairment and Promotes Brain Senescence in CADASIL.
Article in CNS neuroscience & therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- MRI markers of brain fluid dynamics link reduced blood-brain barrier water exchange rate to disease severity in CADASIL.European stroke journal · 2026Article
- Unexpected widespread amyloid PET positivity in a patient with CADASIL.Journal of neurology · 2026Article
- Age-dependent vascular and neurological characteristics of CADASIL are recapitulated in Notch3 mutant zebrafish, implicating a role for type IV collagen in disease progression.Acta neuropathologica communications · 2026Article
- NOTCH3 Mutations in CADASIL: a multicellular perspective on neurodegeneration.Cell communication and signaling : CCS · 2026Review
- The glymphatic system in neurodegenerative diseases and brain tumors: mechanistic insights, biomarker advances, and therapeutic opportunities.Acta neuropathologica communications · 2025Review
- Signaling pathways and molecular mechanisms involved in the onset and progression of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); a focus on Notch3 signaling.The journal of headache and pain · 2025Review
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Authors and funding
17 authors.
Funding
Abstract
aimsThe 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.
methodsWe assessed glymphatic influx and efflux function in CADASIL mouse models (Notch3
resultsCADASIL 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.
conclusionWe propose that to improve glymphatic function by reinforcing AQP4 expression is a promising therapeutic strategy in CADASIL.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.