Exploring the role of the plasminogen activator system in microglial activation and neuronal degeneration

Tissue plasminogen activator (tPA) is a 68 kDa serine protease which catalyzes the conversion of plasminogen to plasmin. This initiates a potent proteolytic cascade which leads to fibrinolysis. Although tPA was thought to be primarily a fibrinolytic enzyme, its expression in many tissues led researchers to investigate whether tPA had functions other than hemostasis.; In the hippocampus, tPA is made by neurons and microglia, the CNS macrophage (Tsirka et al., 1995). Activated microglia are thought to be involved in many neuropathologies (Wood, 1995). Tsirka and colleagues decided to investigate whether tPA may play a role in microglial activation following excitotoxic injury. tPA-deficient mice (tPA--/--) were found to be resistant to excitotoxin-induced neurodegeneration and displayed an attenuation of microglial activation (Tsirka et al., 1995).; Here I show that plasminogen-deficient mice (plg--/-- ) are also resistant to excitotoxin-induced neurodegeneration, indicating the dependence of plasminogen activation in excitotoxicity. This enzymatic reaction is required at or near the time of injury and the inhibition of either tPA or plasmin protects hippocampal neurons from the effects of excitotoxins. In the brain, plasminogen activation may initiate a proteolytic cascade which eventually leads to neuronal death.; tPA affects microglial activation independently of plasmin generation. In pig--/-- mice, microglia become activated normally after excitotoxin injection. Cell culture and in vivo experiments demonstrate that tPA mediates microglial activation via a non-proteolytic mechanism. Therefore, tPA acts as a cytokine in the CNS. The inhibition of microglial activation diminishes secretion of tPA and is neuroprotective. This suggests that activated microglia participate in excitotoxin-induced neurodegeneration. Thus, the tPA released from microglia may be involved in triggering neuronal death.; A model of microglial-neuronal cross-talk during excitotoxic injury can be proposed: (1){A0}neurons depolarize due to the excitotoxin; (2){A0}this depolarization leads to tPA release; (3){A0}neuronal tPA mediates microglial activation; (4) activated microglia release tPA; (5){A0}injured neurons release plasminogen; (6){A0}neuronal plasminogen is activated by microglial tPA and (7){A0}the generation of plasmin initiates a proteolytic cascade which results in neuronal death. According to this model, therapies which block any of these steps may be beneficial in the treatment of many neurodegenerative diseases.