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

• Type of Material: Article
• Authors: Fang Wu, Emory University; Marcela Catano, Emory University; Ramiro Echeverry, Emory University; Enrique Torre, Emory University; Woldeab B. Haile, Emory University; Jie An, Emory University; Changhua Chen, Emory University; Lihong Cheng, Emory University; Andrew Nicholson, Emory University; Frank Tong, Emory University; Jaekeun Park, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2014-10-22
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2014 the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.5309-13.2014
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0270-6474
• Volume: 34
• Issue: 43
• Start Page: 14219
• End Page: 14232
• Grant/Funding Information: This work has been supported in part by National Institutes of Health Grants NS-062073 (to M.Y.) and NS-079331 (to M.Y.) and VA Merit Award BX000474 (to M.Y.).
• Keywords: recovery; cerebral ischemia; stroke; urokinase-type plasminogen activator
• Research Categories: Biology, Neuroscience; Health Sciences, General

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.