Dementia Research Group, Institute of Clinical Neurosciences, Clinical Sciences at North Bristol, Bristol University, Bristol, UK.
J Cell Mol Med. 2012 Apr;16(4):865-76. doi: 10.1111/j.1582-4934.2011.01394.x.
Accumulation and deposition of Aβ is one of the main neuropathological hallmarks of Alzheimer's disease (AD) and impaired Aβ degradation may be one mechanism of accumulation. Plasmin is the key protease of the plasminogen system and can cleave Aβ. 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 α2-antiplasmin and α2-macroglobulin. Here, we investigate the mRNA levels of the activators and inhibitors of the plasminogen system and the protein levels of tPA, neuroserpin and α2-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 α2-antiplasmin protein levels were measured by ELISA. The activators and inhibitors were present mainly in neurons and α2-antiplasmin was also associated with Aβ plaques in AD brain tissue. tPA, uPA, PAI-1 and α2-antiplasmin mRNA were all significantly increased in AD compared to controls, as were tPA and α2-antiplasmin protein, whereas neuroserpin mRNA and protein were significantly reduced. α2-macroglobulin mRNA was not significantly altered in AD. The increases in tPA, uPA, PAI-1 and α2-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.
β淀粉样蛋白（Aβ）的积累和沉积是阿尔茨海默病（AD）的主要神经病理学特征之一，Aβ降解受损可能是其积累的机制之一。纤溶酶是纤溶酶原系统的关键蛋白酶，可切割 Aβ。纤溶酶原通过组织型纤溶酶原激活物（tPA）和尿激酶型纤溶酶原激活物（uPA）转化为纤溶酶。这些激活物受抑制剂的调节，包括纤溶酶原激活物抑制剂-1（PAI-1）和神经丝氨酸蛋白酶抑制剂（neuroserpin）。纤溶酶也受到包括α2-抗纤溶酶和α2-巨球蛋白在内的抑制剂的调节。在这里，我们研究了纤溶酶原系统的激活剂和抑制剂的 mRNA 水平以及 tPA、neuroserpin 和α2-抗纤溶酶在 AD 死后脑组织和对照脑组织中的蛋白水平。通过免疫过氧化物酶染色评估了激活剂和抑制剂在人脑切片中的分布。通过实时 PCR 对 20 例 AD 和 20 例对照脑组织进行了 mRNA 测量。在 38 例 AD 和 38 例对照大脑的扩展队列中，通过 ELISA 测量 tPA、neuroserpin 和α2-抗纤溶酶蛋白水平。激活剂和抑制剂主要存在于神经元中，并且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α2-抗纤溶酶的 mRNA 均显著增加，tPA 和α2-抗纤溶酶蛋白也是如此，而 neuroserpin 的 mRNA 和蛋白则显著降低。AD 中α2-巨球蛋白的 mRNA 没有明显改变。tPA、uPA、PAI-1 和α2-抗纤溶酶的增加可能相互抵消，因此 AD 中纤溶酶的活性没有明显改变，但增加的 tPA 也可能影响突触可塑性、兴奋性神经元死亡和细胞凋亡。
