ArticleThe Journal of clinical investigation2009
Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells.
Article in The Journal of clinical investigation, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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
114 citing papers in PubMed, 1 synthesis or guideline pooled it, 174 citations in OpenAlex.
- Potential Role of the Gut Microbiome in ALS: A Systematic Review.Biological research for nursing · 2018Pooled it
- Trial
- Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers.Current pharmaceutical design · 2013Trial
- Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock.Critical care (London, England) · 2010Trial
- Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.Science advances · 2025Article
- Cellular and molecular mechanisms of the blood-brain barrier dysfunction in neurodegenerative diseases.Fluids and barriers of the CNS · 2024Review
- Characterizing Modulators of Protease-activated Receptors with a Calcium Mobilization Assay Using a Plate Reader.Journal of visualized experiments : JoVE · 2024Article
- Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.Cell death discovery · 2024Article
- Review
- Cytoprotective E-WE thrombin reduces disease severity in a murine model of relapsing-remitting multiple sclerosis.American journal of physiology. Cell physiology · 2024Article
- Effects of Acetyl-L-Carnitine on Oxidative Stress in Amyotrophic Lateral Sclerosis Patients: Evaluation on Plasma Markers and Members of the Neurovascular Unit.Antioxidants (Basel, Switzerland) · 2023Article
- 3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina.International journal of molecular sciences · 2023Article
- Review
- Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2023Review
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Taking Advantages of Blood-Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?Journal of personalized medicine · 2022Review
- The blood-brain barrier in aging and neurodegeneration.Molecular psychiatry · 2022Review
- Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies.NeuroSci · 2022Review
- Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C.The Journal of experimental medicine · 2022Article
54 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 5 institutions in 3 countries.
Funding
Abstract
Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood-spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS.
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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.