Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
Department of Biology and Biotechnology, University of Pavia, Pavia, Italy; Scuola Universitaria Superiore, IUSS, Pavia, Italy.
Cell Signal. 2018 Dec;52:95-102. doi: 10.1016/j.cellsig.2018.08.017. Epub 2018 Aug 30.
Amyloid precursor protein (APP) is the precursor of amyloid β (Aβ) peptides, whose accumulation in the brain is associated with Alzheimer's disease. APP is also expressed on the platelet surface and Aβ peptides are platelet agonists. The physiological role of APP is largely unknown. In neurons, APP acts as an adhesive receptor, facilitating integrin-mediated cell adhesion, while in platelets it regulates coagulation and venous thrombosis. In this work, we analyzed platelets from APP KO mice to investigate whether membrane APP supports platelet adhesion to physiological and pathological substrates. We found that APP-null platelets adhered and spread normally on collagen, von Willebrand Factor or fibrinogen. However, adhesion on immobilized Aβ peptides Aβ, Aβ and Aβ was completely abolished in platelets lacking APP. By contrast, platelet activation and aggregation induced by Aβ peptides occurred normally in the absence of APP. Adhesion of APP-transfected HEK293 to Aβ peptides was significantly higher than that of control cells expressing low levels of APP. Co-coating of Aβ and Aβ with collagen strongly potentiated platelet adhesion when whole blood from wild type mice was perfused at arterial shear rate, but had no effects with blood from APP KO mice. These results demonstrate that APP selectively mediates platelet adhesion to Aβ under static condition but not platelet aggregation, and is responsible for Aβ-promoted potentiation of thrombus formation under flow. Therefore, APP may facilitate an early step in thrombus formation when Aβ peptides accumulate in cerebral vessel walls or atherosclerotic plaques.
淀粉样前体蛋白（APP）是淀粉样 β 肽（Aβ）的前体，其在大脑中的积累与阿尔茨海默病有关。APP 也表达在血小板表面，Aβ 肽是血小板激动剂。APP 的生理作用在很大程度上尚不清楚。在神经元中，APP 作为黏附受体起作用，促进整合素介导的细胞黏附，而在血小板中，它调节凝血和静脉血栓形成。在这项工作中，我们分析了 APP KO 小鼠的血小板，以研究膜 APP 是否支持血小板黏附到生理和病理底物上。我们发现，APP 缺失的血小板在胶原、血管性血友病因子或纤维蛋白原上正常黏附和铺展。然而，在缺乏 APP 的血小板中，对固定化 Aβ 肽 Aβ、Aβ 和 Aβ 的黏附完全被消除。相比之下，在缺乏 APP 的情况下，Aβ 肽诱导的血小板激活和聚集正常发生。APP 转染的 HEK293 对 Aβ 肽的黏附明显高于表达低水平 APP 的对照细胞。当用野生型小鼠的全血在动脉剪切速率下灌注时，Aβ 和 Aβ 与胶原的共涂层强烈增强血小板黏附，但在 APP KO 小鼠的血液中没有作用。这些结果表明，APP 选择性地上调血小板在静态条件下对 Aβ 的黏附，但不调节血小板聚集，并且负责在流动条件下 Aβ 促进血栓形成的增强。因此，当 Aβ 肽在脑血管壁或动脉粥样硬化斑块中积累时，APP 可能有助于血栓形成的早期步骤。
