Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.
J Alzheimers Dis. 2012;32(3):599-608. doi: 10.3233/JAD-2012-120820.
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, tau tangles, brain atrophy, and vascular pathology. Vascular defects include cerebrovascular dysfunction, decreased cerebral blood flow, and blood brain barrier (BBB) disruption, among others. Here, we review the evidence that links Aβ with the vascular pathology present in AD, with a specific focus on the hemostatic system and the clotting protein fibrinogen. Fibrinogen is normally found circulating in blood, but in AD it deposits with Aβ in the brain parenchyma and cerebral blood vessels. We found that Aβ and fibrin(ogen) interact, and their binding leads to increased fibrinogen aggregation, Aβ fibrillization, and the formation of degradation-resistant fibrin clots. Decreasing fibrinogen levels not only lessens cerebral amyloid angiopathy and BBB permeability, but it also reduces microglial activation and improves cognitive performance in AD mouse models. Moreover, a prothrombotic state in AD is evidenced by increased clot formation, decreased fibrinolysis, and elevated levels of coagulation factors and activated platelets. Abnormal deposition and persistence of fibrin(ogen) in AD may result from Aβ-fibrin(ogen) binding and altered hemostasis and could thus contribute to Aβ deposition, decreased cerebral blood flow, exacerbated neuroinflammation, and eventual neurodegeneration. Blocking the interaction between fibrin(ogen) and Aβ may be a promising therapeutic target for AD.
阿尔茨海默病（AD）的特征是淀粉样β（Aβ）斑块、tau 缠结、脑萎缩和血管病理学。血管缺陷包括脑血管功能障碍、脑血流减少和血脑屏障（BBB）破坏等。在这里，我们回顾了将 Aβ 与 AD 中存在的血管病理学联系起来的证据，特别关注止血系统和凝血蛋白纤维蛋白原。纤维蛋白原通常在血液中循环，但在 AD 中，它与 Aβ 在脑实质和脑血管中沉积。我们发现 Aβ 和纤维蛋白原相互作用，它们的结合导致纤维蛋白原聚集增加、Aβ 纤维形成和降解抗性纤维蛋白凝块的形成。降低纤维蛋白原水平不仅减轻了脑淀粉样血管病和 BBB 通透性，还减少了小胶质细胞的激活，并改善了 AD 小鼠模型的认知表现。此外，AD 中的血栓形成状态表现为血栓形成增加、纤维蛋白溶解减少以及凝血因子和活化血小板水平升高。AD 中纤维蛋白原的异常沉积和持续存在可能是由于 Aβ-纤维蛋白原结合以及止血功能改变所致，因此可能导致 Aβ 沉积、脑血流减少、神经炎症加剧和最终神经退行性变。阻断纤维蛋白原和 Aβ 之间的相互作用可能是 AD 的一个有前途的治疗靶点。
