Activators and inhibitors of the plasminogen system in Alzheimer's disease
Activators and inhibitors of the plasminogen system in Alzheimer's disease
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DOI：
10.1111/j.1582-4934.2011.01394.x
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发表时间：
2012-04-01
影响因子：
5.3
通讯作者：
Love, Seth
中科院分区：
文献类型：
--
作者：
Barker, Rachel;Kehoe, Patrick G.;Love, Seth
Aβ 的积累和沉积是阿尔茨海默病 (AD) 的主要神经病理学标志之一，Aβ 降解受损可能是积累的机制之一。纤溶酶是纤溶酶原系统的关键蛋白酶，可以裂解 Aβ。纤溶酶由纤溶酶原通过组织纤溶酶原激活剂 (tPA) 和尿激酶型纤溶酶原激活剂 (uPA) 激活。激活剂受抑制剂调节，包括纤溶酶原激活剂抑制剂-1 (PAI-1) 和神经丝氨酸蛋白酶抑制剂。纤溶酶还受到α2-抗纤溶酶和α2-巨球蛋白等抑制剂的调节。在这里，我们研究了死后 AD 和对照脑组织中纤溶酶原系统激活剂和抑制剂的 mRNA 水平以及 tPA、神经丝氨酸蛋白酶抑制剂和 a2-抗纤溶酶的蛋白质水平。通过免疫过氧化物酶染色评估人脑切片中激活剂和抑制剂的分布。通过实时 PCR 对 20 个 AD 和 20 个对照大脑进行 mRNA 测量。在由 38 个 AD 和 38 个对照大脑组成的扩展队列中，通过 ELISA 测量了 tPA、神经丝氨酸蛋白酶抑制剂和 a2-抗纤溶酶蛋白水平。激活剂和抑制剂主要存在于神经元中，α2-抗纤溶酶也与 AD 脑组织中的 Aβ 斑块相关。与对照组相比，AD 中 tPA、uPA、PAI-1 和 a2-抗纤溶酶 mRNA 均显着增加，tPA 和 a2-抗纤溶酶蛋白也是如此，而神经丝氨酸蛋白酶抑制剂 mRNA 和蛋白质则显着减少。 AD 中α2-巨球蛋白 mRNA 没有显着改变。 tPA、uPA、PAI-1 和 a2-抗纤溶酶的增加可能相互抵消，因此 AD 中纤溶酶活性不会显着改变，但 tPA 增加也可能影响突触可塑性、兴奋毒性神经元死亡和细胞凋亡。
Accumulation and deposition of A beta is one of the main neuropathological hallmarks of Alzheimers disease (AD) and impaired A beta degradation may be one mechanism of accumulation. Plasmin is the key protease of the plasminogen system and can cleave A beta. Plasmin is activated from plasminogen by tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). The activators are regulated by inhibitors which include plasminogen activator inhibitor-1 (PAI-1) and neuroserpin. Plasmin is also regulated by inhibitors including a2-antiplasmin and a2-macroglobulin. Here, we investigate the mRNA levels of the activators and inhibitors of the plasminogen system and the protein levels of tPA, neuroserpin and a2-antiplasmin in post-mortem AD and control brain tissue. Distribution of the activators and inhibitors in human brain sections was assessed by immunoperoxidase staining. mRNA measurements were made in 20 AD and 20 control brains by real-time PCR. In an expanded cohort of 38 AD and 38 control brains tPA, neuroserpin and a2-antiplasmin protein levels were measured by ELISA. The activators and inhibitors were present mainly in neurons and a2-antiplasmin was also associated with A beta plaques in AD brain tissue. tPA, uPA, PAI-1 and a2-antiplasmin mRNA were all significantly increased in AD compared to controls, as were tPA and a2-antiplasmin protein, whereas neuroserpin mRNA and protein were significantly reduced. a2-macroglobulin mRNA was not significantly altered in AD. The increases in tPA, uPA, PAI-1 and a2-antiplasmin may counteract each other so that plasmin activity is not significantly altered in AD, but increased tPA may also affect synaptic plasticity, excitotoxic neuronal death and apoptosis.