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The APCs of neuroprotection
Charles T. Esmon, Jonathan D. Glass
Charles T. Esmon, Jonathan D. Glass
Published October 19, 2009
Citation Information: J Clin Invest. 2009;119(11):3205-3207. https://doi.org/10.1172/JCI40682.
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Commentary

The APCs of neuroprotection

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Abstract

Mutations in the enzyme superoxide dismutase 1 (SOD1) have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). In this issue of the JCI, Zhong et al. report that the endogenous anticoagulant activated protein C (APC) is able to cross the blood–spinal cord barrier in mice and signal to both neuronal and non-neuronal cells (see the related article beginning on page 3437). This signaling resulted in the suppression of mutant SOD1 synthesis and retarded disease progression in a murine model of ALS. Here we discuss the potential importance of these data and possible relevance to human neurodegenerative diseases.

Authors

Charles T. Esmon, Jonathan D. Glass

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Figure 1

Potential mechanism for the protection of neural tissue in ALS.

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Potential mechanism for the protection of neural tissue in ALS.
APC bind...
APC binds to the EPCR located in caveolae. Caveolae translocate the endothelium and allow deposition of APC across the BBB, consistent with the results reported in this issue by Zhong et al. (4). Once across the BBB, APC can dissociate from EPCR and signal neuronal cells through activation of PAR1 in a process dependent on PAR3 (4), and this in turn increases the phosphorylation of the nuclear transcription factor Sp1, thereby downregulating the production of mutant SOD1 (mSOD1), a mediator of neuronal damage in this animal model of familial ALS. As described by Zhong et al. (4), APC can also provide neuroprotective effects by reducing leakage through the BBB, inhibiting release of inflammatory cytokines from microglia as well as lessening the oxidative damage to neurons by Hb products entering the extravascular space through the endothelium.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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