Department of Vascular- and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany.
Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
Mol Cell Neurosci. 2024 Sep;130:103952. doi: 10.1016/j.mcn.2024.103952. Epub 2024 Jul 11.
Alzheimer's disease (AD) is the most common form of dementia and characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles and neurodegeneration. Over 80 % of AD patients also exhibit cerebral amyloid angiopathy (CAA). CAA is a cerebrovascular disease caused by deposition of Aβ in the walls of cerebral blood vessels leading to vessel damage and impairment of normal blood flow. To date, different studies suggest that platelet function, including activation, adhesion and aggregation, is altered in AD due to vascular Aβ deposition. For example, the transgenic AD model mice APP23 mice that exhibit CAA and parenchymal Aβ plaques, show pre-activated platelets in the blood circulation and increased platelet integrin activation leading to a pro-thrombotic phenotype in these mice late stages of AD. However, it is still an open question whether or not platelets exhibit changes in their activation profile before they are exposed to vascular Aβ deposits. Therefore, the present study examined platelets from middle-aged transgenic APP23 mice at the age of 8-10 months. At this age, APP23 mice show amyloid plaques in the brain parenchyma but not in the vasculature. Our analyses show that these APP23 mice have unaltered platelet numbers and size, and unaltered surface expression of glycoproteins. However, the number of dense granules in transgenic platelets was increased while the release was unaltered. Male, but not female APP23 mice, exhibited reduced platelet activation after stimulation of the thrombin receptor PAR4 and decreased thrombus stability on collagen under flow conditions ex vivo compared to control mice. In an arterial thrombosis model in vivo, male APP23 mice showed attenuated occlusion of the injured artery compared to controls. These findings provide clear evidence for early changes in platelet activation and thrombus formation in male mice before development of overt CAA. Furthermore, reduced platelet activation and thrombus formation suggest sex-specific differences in platelet physiology in AD that has to be considered in future studies of platelets and their role in AD.
阿尔茨海默病（AD）是最常见的痴呆症形式，其特征是细胞外淀粉样β（Aβ）斑块、细胞内神经原纤维缠结和神经退行性变。超过 80%的 AD 患者还表现出脑淀粉样血管病（CAA）。CAA 是一种脑血管疾病，由 Aβ在脑血管壁中的沉积引起，导致血管损伤和正常血流受损。迄今为止，不同的研究表明，由于血管 Aβ沉积，AD 患者的血小板功能（包括激活、黏附和聚集）发生改变。例如，表现出 CAA 和实质 Aβ斑块的 APP23 转基因 AD 模型小鼠，其血液循环中的血小板表现出预先激活，血小板整合素激活增加，导致这些小鼠 AD 晚期的血栓前表型。然而，血小板在暴露于血管 Aβ沉积物之前是否表现出激活谱的变化，这仍然是一个悬而未决的问题。因此，本研究检查了 8-10 月龄的中年转基因 APP23 小鼠的血小板。在这个年龄，APP23 小鼠的大脑实质中出现淀粉样斑块，但血管中没有。我们的分析表明，这些 APP23 小鼠的血小板数量和大小没有改变，表面糖蛋白的表达也没有改变。然而，转基因血小板中的致密颗粒数量增加，而释放量没有改变。与对照小鼠相比，雄性而非雌性 APP23 小鼠在刺激凝血酶受体 PAR4 后血小板的激活减少，在体外流动条件下胶原上的血栓稳定性降低。在体内动脉血栓形成模型中，与对照小鼠相比，雄性 APP23 小鼠损伤动脉的闭塞程度减弱。这些发现为雄性小鼠在明显的 CAA 发生之前，血小板激活和血栓形成的早期变化提供了明确的证据。此外，血小板激活和血栓形成的减少表明 AD 中血小板生理学的性别特异性差异，这在未来的血小板及其在 AD 中的作用研究中必须考虑。
