Activated protein C in neuroprotection and malaria.

Activated protein C (APC) is a homeostatic coagulation protease with anticoagulant and cytoprotective activities. Focusing on APC's effects in the brain, this review discusses three different scenarios that illustrate how APC functions are intimately affecting the physiology and pathophysiology of the brain. Cytoprotective APC therapy holds promise for the treatment of ischemic stroke, and a recently completed trial suggested that cytoprotective-selective 3K3A-APC reduced bleeding in ischemic stroke patients. In contrast, APC's anticoagulant activity contributes to brain bleeding as shown by the disproportional upregulation of APC generation in cerebral cavernous malformations lesions in mice. However, too little APC generation also contributes to maladies of the brain, such as in case of cerebral malaria where the binding of infected erythrocytes to the endothelial protein C receptor (EPCR) may interfere with the EPCR-dependent functions of the protein C pathway. Furthermore, discoveries of new activities of APC such as the inhibition of the NLRP3-mediated inflammasome and of new applications of APC therapy such as in Alzheimer's disease and graft-versus-host disease continue to advance our knowledge of this important proteolytic regulatory system. APC's many activities or lack thereof are intimately involved in multiple neuropathologies, providing abundant opportunities for translational research.