Laboratory of Neurobiology and Genetics, The Rockefeller University, 1230 York Ave., New York, NY 10065, USA.
Blood. 2012 Apr 5;119(14):3342-51. doi: 10.1182/blood-2011-11-389668. Epub 2012 Jan 11.
Alzheimer disease is characterized by the presence of increased levels of the β-amyloid peptide (Aβ) in the brain parenchyma and cerebral blood vessels. This accumulated Aβ can bind to fibrin(ogen) and render fibrin clots more resistant to degradation. Here, we demonstrate that Aβ(42) specifically binds to fibrin and induces a tighter fibrin network characterized by thinner fibers and increased resistance to lysis. However, Aβ(42)-induced structural changes cannot be the sole mechanism of delayed lysis because Aβ overlaid on normal preformed clots also binds to fibrin and delays lysis without altering clot structure. In this regard, we show that Aβ interferes with the binding of plasminogen to fibrin, which could impair plasmin generation and fibrin degradation. Indeed, plasmin generation by tissue plasminogen activator (tPA), but not streptokinase, is slowed in fibrin clots containing Aβ(42), and clot lysis by plasmin, but not trypsin, is delayed. Notably, plasmin and tPA activities, as well as tPA-dependent generation of plasmin in solution, are not decreased in the presence of Aβ(42). Our results indicate the existence of 2 mechanisms of Aβ(42) involvement in delayed fibrinolysis: (1) through the induction of a tighter fibrin network composed of thinner fibers, and (2) through inhibition of plasmin(ogen)-fibrin binding.
阿尔茨海默病的特征是脑实质和脑血管中β-淀粉样肽 (Aβ) 水平升高。这种积累的 Aβ 可以与纤维蛋白（原）结合，使纤维蛋白凝块更能抵抗降解。在这里，我们证明 Aβ(42) 特异性结合纤维蛋白，并诱导纤维蛋白网络更紧密，纤维更细，对溶解的抵抗力增加。然而，Aβ(42) 诱导的结构变化不可能是溶解延迟的唯一机制，因为覆盖在正常预先形成的凝块上的 Aβ 也结合纤维蛋白并延迟溶解而不改变凝块结构。在这方面，我们表明 Aβ 干扰纤溶酶原与纤维蛋白的结合，这可能会损害纤溶酶的产生和纤维蛋白的降解。事实上，含有 Aβ(42) 的纤维蛋白凝块中组织型纤溶酶原激活物 (tPA) 但不是链激酶的纤溶酶生成速度减慢，而纤溶酶但不是胰蛋白酶的凝块溶解被延迟。值得注意的是，在存在 Aβ(42) 的情况下，纤溶酶和 tPA 的活性以及 tPA 在溶液中依赖纤溶酶原生成的纤溶酶的活性没有降低。我们的结果表明 Aβ(42) 参与延迟纤维蛋白溶解存在 2 种机制：(1) 通过诱导由更细纤维组成的更紧密的纤维蛋白网络，以及 (2) 通过抑制纤溶酶原-纤维蛋白结合。
