Department of Bionano Technology, Gachon University, Seongnam, 1342 Sungnamdaero, Sujeong-Gu, Seongnam, Gyeonggi 461-701, Korea.
Int J Mol Sci. 2019 Jan 24;20(3):496. doi: 10.3390/ijms20030496.
The vast majority of patients with Alzheimer's disease (AD) suffer from impaired cerebral circulation. Substantial evidence indicates that fibrinogen (Fbg) and fibrin clot formation play an important role in this circulatory dysfunction in AD. Fbg interacts with β-amyloid (1-42) (Aβ), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition has been discovered in the brains of AD patients and mouse models. In this study, biochemical approaches and the epitope mapping immunoassay were employed to characterize binding epitopes within the Fbg and complementary epitopes in Aβ. We discovered the Aβ5⁻25 peptide as the most critical region for the interaction, which can be inhibited by specific monoclonal and polyclonal antibodies against the central region of Aβ. Aβ binding to Fbg may block plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of plasmin-resistant fibrin degradation fragments. Our study elucidates the Aβ⁻Fbg interaction that may involve the mechanism by which Aβ⁻Fbg binding delays fibrinolysis by plasmin, providing valuable information in the development of therapeutic approaches for AD.
绝大多数阿尔茨海默病（AD）患者都存在脑循环受损的情况。大量证据表明，纤维蛋白原（Fbg）和纤维蛋白凝块的形成在 AD 中的这种循环功能障碍中起着重要作用。纤维蛋白原与β-淀粉样蛋白（1-42）（Aβ）相互作用，形成不易被纤溶酶分解的异常血凝块，并且在 AD 患者和小鼠模型的大脑中发现了纤维蛋白沉积增加的现象。在这项研究中，我们采用了生化方法和表位作图免疫测定法来鉴定纤维蛋白原中的结合表位和 Aβ 中的互补表位。我们发现 Aβ5-25 肽是相互作用的最关键区域，针对 Aβ 中心区域的特异性单克隆和多克隆抗体可以对此进行抑制。Aβ 与纤维蛋白原的结合可能会阻止纤溶酶在此部位介导的纤维蛋白裂解，导致不易被纤溶酶分解的纤维蛋白降解片段水平升高。我们的研究阐明了 Aβ-纤维蛋白原的相互作用，这可能涉及到 Aβ-纤维蛋白原结合通过纤溶酶延迟纤维蛋白溶解的机制，为 AD 的治疗方法的开发提供了有价值的信息。
