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

Mikko T. Huuskonen, Yaoming Wang, Angeliki Maria Nikolakopoulou, Axel Montagne, Zhonghua Dai, Divna Lazic, Abhay P. Sagare, Zhen Zhao, Jose A. Fernandez, John H. Griffin, Berislav V. Zlokovic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 theWMand illustrate 3K3A-APC's potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.

Original languageEnglish
Article numbere20211372
JournalJournal of Experimental Medicine
Volume219
Issue number1
DOIs
Publication statusPublished - 30 Nov 2021

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