Role of fibrinogen in Alzheimer's disease

项目摘要 纤维蛋白酶是血凝块的主要蛋白质成分，对正常止血至关重要。它也很好- 除了其有益功能外，过量或持续的纤维蛋白可导致或加剧 许多病理状况，包括动脉粥样硬化、类风湿性关节炎、中风、脊髓损伤、多种 硬化、肌肉萎缩、周围神经再生，甚至细菌感染。β-淀粉样蛋白（Aβ）， 一种导致阿尔茨海默病（AD）的肽，以高亲和力与纤维蛋白原结合。由于这种 在相互作用中，Aβ诱导的纤维蛋白凝块具有异常结构并抵抗降解。持续性纤维蛋白 大脑的血管和/或实质将对神经元功能有害。因此我们建议 探讨纤维蛋白对AD发病机制的影响。 我们已经发现，降低AD小鼠模型中的纤维蛋白原水平导致减少的病理学和更好的治疗效果。 认知能力然而，纤维蛋白加速神经元变性的机制仍然存在， 未知存在两种可能性：1）闭塞-纤维蛋白凝块沉积在血管和血管周围 空间，导致血流量减少，Aβ积聚增加，以及由于剥夺 氧和营养素;和2）炎症-纤维蛋白沉积物驱动慢性炎症状态，导致 细胞损伤 本申请的中心假设是，持续的，结构异常的纤维蛋白凝块形成于血管中。 Aβ的存在有助于在AD中观察到的炎症和神经变性。我们会研究 纤维蛋白对AD患者和小鼠AD发病机制的影响，使用离体凝血试验、遗传学/成像， 小鼠模型和人体样本的生化分析。这些研究可能为新的 AD患者的诊断和治疗。

PROJECT SUMMARY Fibrin is the major protein component of blood clots and is critical for normal hemostasis. It is also well- established that in addition to its beneficial function, excessive or persistent fibrin can lead to or exacerbate many pathological conditions, including atherosclerosis, rheumatoid arthritis, stroke, spinal cord injury, multiple sclerosis, muscular dystrophy, peripheral nerve regeneration, and even bacterial infection. Beta-amyloid (Aβ), a peptide that contributes to Alzheimer’s disease (AD), binds to fibrinogen with high affinity. As a result of this interaction, Aβ-induced fibrin clots have an abnormal structure and resist degradation. Persistent fibrin in the brain’s blood vessels and/or the parenchyma would be deleterious to neuronal function. We therefore propose to investigate how fibrin affects the pathogenesis of AD. We have found that reducing fibrinogen levels in AD mouse models results in reduced pathology and better cognitive ability. However, the mechanism by which fibrin accelerates neuronal degeneration remains unknown. Two likely possibilities exist: 1) Occlusion – fibrin clots are deposited in the vascular and perivascular space, resulting in reduced blood flow, increased Aβ accumulation, and neuronal damage due to deprivation of oxygen and nutrients; and 2) Inflammation – fibrin deposits drive a chronic inflammatory state that leads to cellular damage. The central hypothesis of this application is that the persistent, structurally abnormal fibrin clots formed in the presence of Aβ contribute to the inflammation and neurodegeneration observed in AD. We will examine the effects of fibrin on AD pathogenesis in AD patients and mice using ex vivo clotting assays, genetics/imaging in a mouse model, and biochemical analysis of human samples. These studies may provide insights for new diagnostics and therapies for AD patients.