An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus.
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.
Tsirka
S E
SE
Department of Pharmacology, University Medical Center at Stony Brook, New York 11794-8651, USA.
Rogove
A D
AD
Bugge
T H
TH
Degen
J L
JL
Strickland
S
S
D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D004351:Drug Resistance; D010450:Endopeptidases / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000633:toxicity*; D005110:Extracellular Space / Q000378:metabolism*; D005341:Fibrinolysin / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007608:Kainic Acid / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009928:Organ Specificity; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D018076:DNA, Complementary; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000979:alpha-2-Antiplasmin; D010958:Plasminogen; D010450:Endopeptidases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D007608:Kainic Acid