Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C

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  • Mikko T. Huuskonen
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Yaoming Wang
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Angeliki Maria Nikolakopoulou
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Axel Montagne
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Zhonghua Dai
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Divna Lazic
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Abhay P. Sagare
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Zhen Zhao
    Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1
  • Jose A. Fernandez
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 3
  • John H. Griffin
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 3
  • Berislav V. Zlokovic
    The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 2

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<jats:p>Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC’s suppression of post–WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC’s potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.</jats:p>

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