Impact of platelets in the progression of Alzheimers disease

血小板对阿尔茨海默病进展的影响

• 批准号: 392381697
• 负责人: Professorin Dr. Margitta Elvers
• 金额: --
• 依托单位: Klinik für Gefäß- und Endovaskularchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392381697?language=en
• 关键词: Impact; platelets; progression; Alzheimers; disease

Platelets are essential mediators of hemostasis and arterial thrombosis but also play asignificant role in inflammatory degenerative diseases such as Alzheimers disease.Alzheimers disease is characterized by deposits of neurotoxic amyloid plaques resulting in neuron loss and cognitive capability. Beside brain parenchyma, peripheral tissue is affected by the disease leading to alterations in the vascular system that induces amyloid deposits in cerebral vessels identified as cerebral Amyloidangiopathy (CAA). On the basis of vascular amyloid deposits further complications by vessel alterations and hypoperfusion play a dominant role beside the neurotoxic effects of amyloid plaques. Besides, Alzheimers disease is strongly associated with cardiovascular diseases. Substantial players in these diseases are platelets that express the Amyloid Precursor Protein (APP) and generate Amyloid beta (Abeta) peptides. In preliminary studies we were able to show that stimulation with soluble Abeta leads to adhesion, activation and aggregation of platelets in vitro und in vivo. APP23 transgenic mice (Alzheimer model mice) display a pro-thrombotic phenotype and an enhanced risk of cerebro- and cardiovascular complications. Moreover, platelets are able to modulate solubleAbeta40 resulting in fibrillar Abeta aggregation. Binding of synthetic monomeric Abeta40 to integrin alphaIIbbeta3 plays a central role in these processes and stimulates the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets both playing a crucial role in platelet-mediated Abeta aggregation. A significant reduction of vascular amyloid deposits by treatment of APP23 transgenic mice with the platelet Inhibitor Clopidogrel provided strong evidence that platelets directly contribute to CAA by promoting the formation of Abeta aggregates and that Abeta, in turn, activates platelets, creating a feed-forward loop. To date it is completely unclear, if the proteins playing a role in platelet-mediated effects of Abeta aggregation in transgenic mice, are of relevance in patients with Alzheimers disease and if anti-platelet therapy may alleviate fibril formation in cerebral vessels of these patients. The impact of platelets in the formation of parenchymal plaques as well as the consequences of Clopidogrel treatment on cognitive function of APP23 mice is likewise unknown. Therefore the aim of the project is to elucidate the role of platelets in Alzheimers disease to improve the understanding of the patho-physiological relevance of platelet-mediated cellular responses in transgenic mice and patients with Alzheimers disease. We expect to gain a new clear strategy to control platelet activity like that platelet-associated factors that account for the progression of the disease can be modulated to delay the progression of Alzheimers disease. Moreover, the analysis of platelet function might serve as a new biomarker for an early and safe diagnosis of Alzheimers disease.

血小板是止血和动脉血栓形成的重要介质，但在阿尔茨海默病等炎性退行性疾病中也起着重要作用。阿尔茨海默病的特点是神经毒性淀粉样斑块沉积，导致神经元丧失和认知能力。除了脑实质外，外周组织也受到疾病的影响，导致血管系统的改变，在脑血管中诱发淀粉样蛋白沉积，被称为脑淀粉样血管病（CAA）。在血管淀粉样蛋白沉积的基础上，除了淀粉样蛋白斑块的神经毒性作用外，由血管改变和灌注不足引起的进一步并发症也起主导作用。此外，阿尔茨海默病与心血管疾病密切相关。这些疾病的主要参与者是表达淀粉样蛋白前体蛋白（APP）并产生β淀粉样蛋白（Abeta）肽的血小板。在初步研究中，我们能够证明用可溶性β刺激可导致血小板在体内和体外的粘附、活化和聚集。APP23转基因小鼠（阿尔茨海默病模型小鼠）显示出促血栓表型和大脑和心血管并发症的风险增加。此外，血小板能够调节可溶性abeta40，导致纤维状的abeta40聚集。合成单体Abeta40与整合素alphaIIbbeta3结合在这些过程中起核心作用，并刺激血小板分泌二磷酸腺苷（ADP）和伴侣蛋白聚集蛋白，两者在血小板介导的Abeta聚集中起关键作用。用血小板抑制剂氯吡格雷治疗APP23转基因小鼠，血管淀粉样蛋白沉积显著减少，这有力地证明了血小板通过促进Abeta聚集体的形成直接促进CAA，而Abeta反过来激活血小板，形成一个前驱循环。迄今为止，还完全不清楚在转基因小鼠血小板介导的β聚集效应中发挥作用的蛋白质是否与阿尔茨海默病患者相关，以及抗血小板治疗是否可以减轻这些患者脑血管纤维的形成。血小板对实质斑块形成的影响以及氯吡格雷治疗对APP23小鼠认知功能的影响同样未知。因此，该项目的目的是阐明血小板在阿尔茨海默病中的作用，以提高对血小板介导的细胞反应在转基因小鼠和阿尔茨海默病患者中的病理生理相关性的理解。我们希望获得一种新的明确的策略来控制血小板活性，就像血小板相关因素可以调节疾病的进展，从而延缓阿尔茨海默病的进展。此外，血小板功能的分析可能作为早期和安全诊断阿尔茨海默病的新的生物标志物。