AN EXTRACELLULAR PROTEOLYTIC CASCADE PROMOTES NEURONAL DEGENERATION IN THE MOUSE HIPPOCAMPUS

Mice lacking the serine protease tissue plasminogen activator (tPA) ar e resistant to excitotoxin-mediated hippocampal neuronal degeneration. We have used genetic and cellular analyses to study the role of tPA i n neuronal cell death. Mice deficient for the zymogen plasminogen, a k nown substrate for tPA, are also resistant to excitotoxins, implicatin g an extracellular proteolytic cascade in degeneration. The two known components of this cascade, tPA and plasminogen, are both synthesized in the mouse hippocampus. tPA mRNA and protein are present in neurons and microglia, whereas plasminogen mRNA and protein are found exclusiv ely in neurons. tPA-deficient mice exhibit attenuated microglial activ ation as a reaction to neuronal injury. In contrast, the microglial re sponse of plasminogen-deficient mice was comparable to that of wild-ty pe mice, suggesting a tPA-mediated, plasminogen-independent pathway fo r activation of microglia. Infusion of inhibitors of the extracellular tPA/plasmin proteolytic cascade into the hippocampus protects neurons against excitotoxic injury, suggesting a novel strategy for interveni ng in neuronal degeneration.