Canobbio Ilaria, Guidetti Gianni F, Oliviero Barbara, Manganaro Daria, Vara Dina, Torti Mauro, Pula Giordano
*Department of Biology and Biotechnology, Unit of Biochemistry, University of Pavia, Pavia 27100, Italy.
†Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia 27100, Italy.
Biochem J. 2014 Sep 15;462(3):513-23. doi: 10.1042/BJ20140307.
Alzheimer's disease is associated with the accumulation of Aβ (amyloid β)-peptides in the brain. Besides their cytotoxic effect on neurons, Aβ-peptides are thought to be responsible for the atherothrombotic complications associated with Alzheimer's disease, which are collectively known as cerebrovascular disease. In the present study, we investigated the effect of Aβ-peptides on human platelet signal transduction and function. We discovered that the 25-35 domain of Aβ-peptides induce an increase in platelet intracellular Ca2+ that stimulates α-granule and dense granule secretion and leads to the release of the secondary agonist ADP. Released ADP acts in an autocrine manner as a stimulant for critical signalling pathways leading to the activation of platelets. This includes the activation of the protein kinases Syk, protein kinase C, Akt and mitogen-activated protein kinases. Ca2+-dependent release of ADP is also the main component of the activation of the small GTPase Rap1b and the fibrinogen receptor integrin αIIbβ3, which leads to increased platelet aggregation and increased thrombus formation in human whole blood. Our discoveries complement existing understanding of cerebrovascular dementia and suggest that Aβ-peptides can induce vascular complications of Alzheimer's disease by stimulating platelets in an intracellular Ca2+-dependent manner. Despite a marginal ADP-independent component suggested by low levels of signalling activity in the presence of apyrase or P2Y receptor inhibitors, Ca2+-dependent release of ADP by Aβ-peptides clearly plays a critical role in platelet activation. Targeting ADP signalling may therefore represent an important strategy to manage the cerebrovascular component of Alzheimer's disease.
阿尔茨海默病与大脑中β淀粉样蛋白（Aβ）肽的积累有关。除了对神经元具有细胞毒性作用外，Aβ肽还被认为是导致阿尔茨海默病相关动脉粥样血栓形成并发症的原因，这些并发症统称为脑血管疾病。在本研究中，我们研究了Aβ肽对人血小板信号转导和功能的影响。我们发现，Aβ肽的25 - 35结构域可诱导血小板细胞内Ca2+增加，刺激α颗粒和致密颗粒分泌，并导致二级激动剂ADP的释放。释放的ADP以自分泌方式作为导致血小板激活的关键信号通路的刺激物。这包括蛋白激酶Syk、蛋白激酶C、Akt和丝裂原活化蛋白激酶的激活。Ca2+依赖的ADP释放也是小GTPase Rap1b和纤维蛋白原受体整合素αIIbβ3激活的主要组成部分，这导致人全血中血小板聚集增加和血栓形成增加。我们的发现补充了对脑血管性痴呆的现有认识，并表明Aβ肽可通过以细胞内Ca2+依赖的方式刺激血小板来诱导阿尔茨海默病的血管并发症。尽管在存在apyrase或P2Y受体抑制剂的情况下，低水平的信号活性提示存在少量不依赖ADP的成分，但Aβ肽Ca2+依赖的ADP释放显然在血小板激活中起关键作用。因此，靶向ADP信号传导可能是管理阿尔茨海默病脑血管成分的重要策略。
