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Volume 17, Number 2, Issue of January 15, 1997 pp. 543-552
Copyright ©1997 Society for NeuroscienceAn Extracellular Proteolytic Cascade Promotes Neuronal Degeneration in the Mouse Hippocampus
Received Aug. 26, 1996; revised Oct. 15, 1996; accepted Oct. 23, 1996.
Stella E. Tsirka1, Andrew D. Rogove1, 3, Thomas H. Bugge4, Jay L. Degen4, and Sidney Strickland1, 2 1 Department of Pharmacology, 2 Program in Genetics, and 3 Medical Scientist Training Program, University Medical Center at Stony Brook, Stony Brook, New York 11794-8651, and 4 Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229
Mice lacking the serine protease tissue plasminogen activator (tPA) are resistant to excitotoxin-mediated hippocampal neuronal degeneration. We have used genetic and cellular analyses 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 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 exclusively in neurons. tPA-deficient mice exhibit attenuated microglial activation as a reaction to neuronal injury. In contrast, the microglial response of plasminogen-deficient mice was comparable to that of wild-type mice, suggesting a tPA-mediated, plasminogen-independent pathway for 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 intervening in neuronal degeneration.
Key words: tPA; kainate; plasminogen; hippocampus; neurons; microglia; mouse
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