Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells
Open accessAbstract
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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Studies in SOD1 transgenic mice expressing dismutase-active (G93A and G37R) and dismutase-inactive (G85R) mutations have suggested that BSCB breakdown occurs before motor neuron injury.
“Studies in SOD1 transgenic mice expressing dismutase-active (G93A and G37R) and dismutase-inactive (G85R) mutations have suggested that BSCB breakdown occurs before motor neuron injury (194, 415, 651, 687, 688).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [688]
The section on selective SOD1 G37R excision reports previously observed presymptomatic spinal-capillary damage in SOD1 mutant mice and a leaky BSCB in G37R mice at disease onset. It does not establish that BSCB breakdown precedes motor-neuron injury across G93A, G37R, and G85R mice; the following paragraph says the timing of BSCB disruption remains to be established. Page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredBBB disruption including diminished levels of tight junction proteins, IgG and hemosiderin perivascular deposits, and GLUT1 reduction has been shown to precede neuroinflammation, motor neuron loss, and motor impairment in different types of SOD1 mutants.
“BBB disruption including diminished levels of TJ proteins, immunoglobulin G (IgG) and hemosiderin perivascular deposits, and GLUT1 reduction has been shown to precede neuroinflammation, motor neuron loss, and motor impairment in different types of SOD1 mutants (415, 687, 688).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [688]
The Introduction says blood–spinal cord barrier microvessels are damaged early in SOD1-mutant disease, and the section ‘Neuroprotection by APC reduces hemoglobin and ROS toxicity’ reports reduced ZO-1 and occludin alongside IgG leakage and hemosiderin deposits in SOD1 G93A mice. Our copy does not report GLUT1 reduction or establish that all these changes precede neuroinflammation, motor-neuron loss, and motor impairment across different SOD1 mutants. The evidence also concerns the blood–spinal cord barrier, rather than specifically the blood–brain barrier. (LLM, conf=0.86)
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- Authors
- Zhong, Z., Ilieva, H., Hallagan, L., Bell, R., Singh, I., Paquette, N., Thiyagarajan, M., Deane, R., Fernandez, J. A., Lane, S., Zlokovic, A. B., Liu, T., Griffin, J. H., Chow, N., Castellino, F. J., Stojanovic, K., Cleveland, D. W., & Zlokovic, B. V.
- Affiliations
- University of Rochester Medicine (US)
- University of California San Diego (US)
- Scripps Research Institute (US)
- University of Notre Dame (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2009-10-19
- Volume
- 119
- Issue
- 11
- Pages
- 3437-49
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2769191
- OpenAlex
- W2140403305
- Cited by
- 176
- References
- 4
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 11 · 2019: 11 · 2018: 7 · 2017: 9 · 2016: 8 · 2015: 8 · 2014: 17 · 2013: 17 · 2012: 15
- FWCI
- 12.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- Ludwig Institute for Cancer Research
- National Institutes of Health (HL63290, HL52246, NS27036, HL73750)
- National Heart, Lung, and Blood Institute (HL63290, R01HL063290, R01HL052246, P01HL073750, HL-73750, HL-52246, R01HL081528, HL81528, R37HL052246)
- National Institute of Neurological Disorders and Stroke (NS 27036, R37NS027036, R01NS027036)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Keywords
- activated protein C, amyotrophic lateral sclerosis, SOD1 mutations, motor neurons, microglia, protease-activated receptor 1, protease-activated receptor 3, Sp1, endothelial protein C receptor, blood-spinal cord barrier, microglial activation, familial ALS, sporadic ALS
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Blood-Brain Barrier, Cell Line, Cell Nucleus, Cells, Cultured, Disease Models, Animal, Endothelium, Fibrinolytic Agents, Male, Motor Neurons, Protein C, Receptors, Cell Surface, Spinal Cord, Superoxide Dismutase, Gene Expression Regulation, Enzymologic, Sp1 Transcription Factor, Microglia, Neuroprotective Agents, Receptors, Proteinase-Activated, Mice
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