ArticleThe Journal of clinical investigation2024
Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 48 citations in OpenAlex.
- Implications of Cranial Arterial Stenosis and Dolichoectasia for Cerebral Small-Vessel Disease Etiopathogenesis: Findings From a Prospective Mild Stroke Cohort.Circulation · 2026Pooled it
- Intracranial aneurysms as a manifestation of premature vascular aging: Cellular senescence, inflammaging, and wall degeneration.Ageing research reviews · 2026Review
- The glymphatic system and Parkinson's disease: a narrative review.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Review
- A collaborative framework for uncovering molecular and cellular drivers of VCID: Foundations for future interventions in dementia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- The Clearance-Centered Bottleneck in Alzheimer's Disease: From Coupled Glymphatic-Lymphatic Circuits to Therapeutic Opportunities.Molecular neurobiology · 2026Review
- A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.Science (New York, N.Y.) · 2026Article
- Small molecule-mediated activation of Notch signal transduction.Cell death & disease · 2026Article
- Glymphatic system impairment in neurological disorders: potential mechanisms and therapeutic targets.Molecular biomedicine · 2026Review
- Proteogenomic Analysis of Coronary Artery Calcification in Human Populations.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- 3D Vessels-on-Chip using isogenic hiPSC-derived VSMCs reveal NOTCH3-driven alterations in brain small vessel disease.Stem cell reports · 2026Article
- Glucose and Lipid Metabolic Mechanisms in Vascular Aging and Related Therapeutic Strategies.Reviews in cardiovascular medicine · 2026Review
- The Effect of Cranio-Cervical Artery Stenosis on Glymphatic System Function in Patients with Cerebral Infarction.Journal of clinical medicine · 2026Article
- NOTCH3 Pathogenic Variant and Risk of Age-Related Macular Degeneration: Findings From the Taiwan Biobank and Small Vessel Disease Registry.Investigative ophthalmology & visual science · 2026Article
- Toward development of a dynamic supramolecular peptide therapy for acute ischemic stroke.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Increased metallopeptidase activity, compromised endothelial integrity and impaired pathogen recognition revealed by transcriptomics inCurrent research in parasitology & vector-borne diseases · 2026Article
- The glymphatic system in neurodegenerative diseases and brain tumors: mechanistic insights, biomarker advances, and therapeutic opportunities.Acta neuropathologica communications · 2025Review
- Reduced SUMOylation impairs NOTCH3 signaling and cell survival in the pathogenesis of CADASIL.Cell communication and signaling : CCS · 2025Article
- Exploring cerebral small vessel disease, choroid plexus, demographics and vascular risk factors that affect glymphatic function.Japanese journal of radiology · 2025Article
- Quantifying Capillary Pericytes In Vivo Links Them to Retinal Vascular Leakage and Potentially Albuminuria: A Pilot Study in Diabetes.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Novel Mutation ofBalkan journal of medical genetics : BJMG · 2025Article
Corrections and comments
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Authors and funding
25 authors at 5 institutions in 2 countries.
Funding
Abstract
Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.
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Registered trials
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.