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Articles, Neurobiology of Disease

Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke

Fang Wu, Marcela Catano, Ramiro Echeverry, Enrique Torre, Woldeab B. Haile, Jie An, Changhua Chen, Lihong Cheng, Andrew Nicholson, Frank C. Tong, Jaekeun Park and Manuel Yepes
Journal of Neuroscience 22 October 2014, 34 (43) 14219-14232; DOI: https://doi.org/10.1523/JNEUROSCI.5309-13.2014
Fang Wu
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Marcela Catano
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Ramiro Echeverry
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Enrique Torre
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Woldeab B. Haile
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Jie An
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
2Department of Pharmacology, Shandong University School of Medicine, 250100 Jinan, China,
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Changhua Chen
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Lihong Cheng
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
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Andrew Nicholson
3Department of Radiology and Imaging Sciences and
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Frank C. Tong
4Departments of Radiology and Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322,
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Jaekeun Park
5Wallace H. Coulter Department of Biomedical Engineering, Emory University, Atlanta, Georgia 30322, and
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Manuel Yepes
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322,
6Department of Neurology, Veterans Affairs Medical Center, Atlanta, Georgia 30349
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Abstract

Spines are dendritic protrusions that receive most of the excitatory input in the brain. Early after the onset of cerebral ischemia dendritic spines in the peri-infarct cortex are replaced by areas of focal swelling, and their re-emergence from these varicosities is associated with neurological recovery after acute ischemic stroke (AIS). Urokinase-type plasminogen activator (uPA) is a serine proteinase that plays a central role in tissue remodeling via binding to the urokinase plasminogen activator receptor (uPAR). We report that cerebral cortical neurons release uPA during the recovery phase from ischemic stroke in vivo or hypoxia in vitro. Although uPA does not have an effect on ischemia- or hypoxia-induced neuronal death, genetic deficiency of uPA (uPA−/−) or uPAR (uPAR−/−) abrogates functional recovery after AIS. Treatment with recombinant uPA after ischemic stroke induces neurological recovery in wild-type and uPA−/− but not in uPAR−/− mice. Diffusion tensor imaging studies indicate that uPA−/− mice have increased water diffusivity and decreased anisotropy associated with impaired dendritic spine recovery and decreased length of distal neurites in the peri-infarct cortex. We found that the excitotoxic injury induces the clustering of uPAR in dendritic varicosities, and that the binding of uPA to uPAR promotes the reorganization of the actin cytoskeleton and re-emergence of dendritic filopodia from uPAR-enriched varicosities. This effect is independent of uPA's proteolytic properties and instead is mediated by Rac-regulated profilin expression and cofilin phosphorylation. Our data indicate that binding of uPA to uPAR promotes dendritic spine recovery and improves functional outcome following AIS.

  • cerebral ischemia
  • recovery
  • stroke
  • urokinase-type plasminogen activator
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The Journal of Neuroscience: 34 (43)
Journal of Neuroscience
Vol. 34, Issue 43
22 Oct 2014
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Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke
Fang Wu, Marcela Catano, Ramiro Echeverry, Enrique Torre, Woldeab B. Haile, Jie An, Changhua Chen, Lihong Cheng, Andrew Nicholson, Frank C. Tong, Jaekeun Park, Manuel Yepes
Journal of Neuroscience 22 October 2014, 34 (43) 14219-14232; DOI: 10.1523/JNEUROSCI.5309-13.2014

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Urokinase-Type Plasminogen Activator Promotes Dendritic Spine Recovery and Improves Neurological Outcome Following Ischemic Stroke
Fang Wu, Marcela Catano, Ramiro Echeverry, Enrique Torre, Woldeab B. Haile, Jie An, Changhua Chen, Lihong Cheng, Andrew Nicholson, Frank C. Tong, Jaekeun Park, Manuel Yepes
Journal of Neuroscience 22 October 2014, 34 (43) 14219-14232; DOI: 10.1523/JNEUROSCI.5309-13.2014
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Keywords

  • cerebral ischemia
  • recovery
  • stroke
  • urokinase-type plasminogen activator

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