Tsirka S E, Rogove A D, Bugge T H, Degen J L, Strickland S
Department of Pharmacology, University Medical Center at Stony Brook, New York 11794-8651, USA.
J Neurosci. 1997 Jan 15;17(2):543-52. doi: 10.1523/JNEUROSCI.17-02-00543.1997.
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.
缺乏丝氨酸蛋白酶组织型纤溶酶原激活剂（tPA）的小鼠对兴奋性毒素介导的海马神经元变性具有抗性。我们利用遗传学和细胞分析方法来研究tPA在神经元细胞死亡中的作用。缺乏纤溶酶原（tPA的一种已知底物）的小鼠对兴奋性毒素也具有抗性，这表明细胞外蛋白水解级联反应参与了变性过程。该级联反应的两个已知成分，tPA和纤溶酶原，均在小鼠海马体中合成。tPA的mRNA和蛋白存在于神经元和小胶质细胞中，而纤溶酶原的mRNA和蛋白仅在神经元中发现。tPA缺陷型小鼠在对神经元损伤的反应中表现出小胶质细胞激活减弱。相比之下，纤溶酶原缺陷型小鼠的小胶质细胞反应与野生型小鼠相当，这表明存在一条由tPA介导、不依赖纤溶酶原的小胶质细胞激活途径。将细胞外tPA/纤溶酶蛋白水解级联反应的抑制剂注入海马体可保护神经元免受兴奋性毒性损伤，这提示了一种干预神经元变性的新策略。
