Chen Z L, Strickland S
Department of Pharmacology, University at Stony Brook, New York 11794-8651, USA.
Cell. 1997 Dec 26;91(7):917-25. doi: 10.1016/s0092-8674(00)80483-3.
Excess excitatory amino acids can provoke neuronal death in the hippocampus, and the extracellular proteases tissue plasminogen activator (tPA) and plasmin (ogen) have been implicated in this death. To investigate substrates for plasmin that might influence neuronal degeneration, extracellular matrix (ECM) protein expression was examined. Laminin is expressed in the hippocampus and disappears after excitotoxin injection. Laminin disappearance precedes neuronal death, is spatially coincident with regions that exhibit neuronal loss, and is blocked by either tPA-deficiency or infusion of a plasmin inhibitor, both of which also block neuronal degeneration. Preventing neuron-laminin interaction by infusion of anti-laminin antibodies into tPA-deficient mice restores excitotoxic sensitivity to their hippocampal neurons. These results indicate that disruption of neuron-ECM interaction via tPA/plasmin catalyzed degradation of laminin sensitizes hippocampal neurons to cell death.
过量的兴奋性氨基酸可引发海马体中的神经元死亡，细胞外蛋白酶组织型纤溶酶原激活物（tPA）和纤溶酶（原）与这种死亡有关。为了研究可能影响神经元变性的纤溶酶底物，检测了细胞外基质（ECM）蛋白的表达。层粘连蛋白在海马体中表达，在注射兴奋性毒素后消失。层粘连蛋白的消失先于神经元死亡，在空间上与出现神经元丢失的区域一致，并且被tPA缺陷或纤溶酶抑制剂的注入所阻断，这两者也都能阻断神经元变性。通过向tPA缺陷小鼠注入抗层粘连蛋白抗体来阻止神经元与层粘连蛋白的相互作用，可恢复其海马神经元对兴奋性毒性的敏感性。这些结果表明，通过tPA/纤溶酶催化的层粘连蛋白降解破坏神经元与ECM的相互作用，会使海马神经元对细胞死亡敏感。
