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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\u2019s suppression of post\u2013WM 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\u2019s potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.<\/jats:p>","DOI":"10.1084\/jem.20211372","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T14:52:07Z","timestamp":1638283927000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7170-3016","authenticated-orcid":true,"given":"Mikko T.","family":"Huuskonen","sequence":"first","affiliation":[{"name":"Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA 1"},{"name":"The Zilkha Neurogenetic Institute, Keck 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