ArticleThe Journal of clinical investigation2021
Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 164 papers, 1 of them a synthesis that pooled it.
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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
164 citing papers in PubMed, 1 synthesis or guideline pooled it, 231 citations in OpenAlex.
- Comprehensive safety analysis of adverse events associated with eptinezumab in migraine treatment.Scientific reports · 2025Pooled it
- A randomized diet-induced weight-loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction.Obesity (Silver Spring, Md.) · 2022Trial
- Role of complement and complement-targeted therapeutics in neurological diseases.Nature reviews. Neurology · 2026Review
- Complement Activation by Post-Translationally Modified Proteins: Links to Chronic Inflammation and Autoimmunity.Immunological reviews · 2026Review
- Temporal profiling of hippocampal astrocyte reactivity reveals persistent GFAP cleavage and complement C3 association after status epilepticus.Brain structure & function · 2026Article
- Vorinostat Mitigates Early Brain Injury Following Subarachnoid Hemorrhage Through Modulation of the C3aR1/TGF-β/Smad Pathway.CNS neuroscience & therapeutics · 2026Article
- Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model.Brain, behavior, and immunity · 2026Article
- Liver-derived complement component 3 promotes the susceptibility to stress-induced depression by impairing blood-brain barrier integrity.Molecular psychiatry · 2026Article
- Exploring peripheral immune mechanisms and potential therapeutic drugs for Alzheimer's disease.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Roles of Microglia in Cerebral Small Vessel Disease.CNS neuroscience & therapeutics · 2026Review
- Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice.Molecular neurodegeneration · 2026Article
- Dysfunction of the neurovascular unit as a temporal driver in Alzheimer's pathogenesis.Translational neurodegeneration · 2026Review
- Targeting microglial C1q alleviates blood-brain barrier disruption in the thalamus after cortical infarction.Journal of neuroinflammation · 2026Article
- Bindarit attenuates brain injury and neuroinflammation in status epilepticus by disrupting C3/C3aR signaling and modulating microglia-astrocyte interactions.Cell communication and signaling : CCS · 2026Article
- Endothelial NADAlzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Early Binding of Anti-Amyloid Antibodies to CAA Drives Complement Activation, Inflammation and ARIA in Mice.bioRxiv : the preprint server for biology · 2026Article
- Early hypoxia-induced secretome remodeling reveals adaptive mechanisms and biomarkers of blood-brain barrier dysfunction in ischemic stroke.Molecular brain · 2026Article
- Neurogenesis and Neuroinflammation in Dialogue: Mapping Gaps, Modulating Microglia, Rewiring Aging.Cells · 2026Review
- The complement system in Alzheimer's disease: mechanisms, biomarkers, and therapeutic implications.Frontiers in immunology · 2026Review
- Increasing complexity in vascular microphysiological systems: considerations and advances for disease modeling.Frontiers in bioengineering and biotechnology · 2026Review
104 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell-specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.
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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.