A tpatplasmin proteolytic cascade promotes neuronal degeneration in the mammalian hippocampus

Tissue plasminogen activator (tPA), a serine protease that converts inactive plasminogen to the active protease plasmin, is expressed in the mouse hippocampus. This expression is increased by procedures that stimulate neuronal activity. To investigate the role of tPA in neuronal processes, we used intracerebral injection of excitotoxins as an exaggerated form of Stimulation. This procedure, which induces neuronal lesions in wild-type animals, shows that mice deficient for tPA are resistant to hippocampal neuronal degeneration. A combination of genetic, cellular, and biochemical analyses has been used to study the role of tPA in neuronal cell death. Mice deficient for the zymogen plasminogen, a known substrate for tPA, are also resistant to excitotoxins, implicating an extracellular proteolytic cascade in degeneration. The two components of this cascade, tPA and plasminogen, are both synthesized in the mouse hippocampus. tPA mRNA is found in neurons and tnicroglia, with microglia contributing the majority of enzymatic activity upon injury. In contrast, plasminogen mRNA is found exclusively in neurons, suggesting a collaboration of neighboring cell types in effecting degeneration. Consistent with the model that extracellular proteolysis is required at the time of excitotoxic injury, infusion of plasminogen activator inhibitor-1 into the hippocampus of wildtype mice confers resistance to excitotoxin-induced neuronal degeneration.