Smith-Swintosky V L, Zimmer S, Fenton J W, Mattson M P
Sanders-Brown Research Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
J Neurochem. 1995 Sep;65(3):1415-8. doi: 10.1046/j.1471-4159.1995.65031415.x.
Amyloid beta-peptide (A beta) is the principal component of neuritic plaques in the brain in Alzheimer's disease (AD). Recent studies revealed that A beta can be neurotoxic by a mechanism involving free radical production and loss of cellular ion homeostasis, thus implicating A beta as a key factor in the pathogenesis of AD. However, other proteins are present in plaques in AD, including the protease thrombin and protease nexin-1 (PN1), a thrombin inhibitor. We therefore tested the hypothesis that thrombin and PN1 modify neuronal vulnerability to A beta toxicity. In dissociated rat hippocampal cell cultures the toxicity of A beta was significantly enhanced by coincubation with thrombin, whereas PN1 protected neurons against A beta toxicity. A beta induced an increase in levels of intracellular peroxides and calcium. Thrombin enhanced, and PN1 attenuated, the accumulation of peroxides and calcium induced by A beta. Taken together, these data demonstrate that thrombin and PN1 have opposing effects on neuronal vulnerability to A beta and suggest that thrombin and PN1 play roles in the pathogenesis of neuronal injury in AD.
淀粉样β肽（Aβ）是阿尔茨海默病（AD）患者大脑中神经炎性斑块的主要成分。最近的研究表明，Aβ可通过涉及自由基产生和细胞离子稳态丧失的机制产生神经毒性，因此表明Aβ是AD发病机制中的关键因素。然而，AD斑块中还存在其他蛋白质，包括蛋白酶凝血酶和蛋白酶抑制因子1（PN1），一种凝血酶抑制剂。因此，我们检验了凝血酶和PN1改变神经元对Aβ毒性易感性的假说。在大鼠海马细胞解离培养物中，与凝血酶共同孵育可显著增强Aβ的毒性，而PN1则保护神经元免受Aβ毒性的影响。Aβ可导致细胞内过氧化物和钙水平升高。凝血酶增强了Aβ诱导的过氧化物和钙的积累，而PN1则减弱了这种积累。综上所述，这些数据表明凝血酶和PN1对神经元对Aβ的易感性具有相反的作用，并提示凝血酶和PN1在AD神经元损伤的发病机制中发挥作用。
