Role of fibrinogen in Alzheimer's disease

纤维蛋白原在阿尔茨海默病中的作用

• 批准号: 10054200
• 负责人: ERIN H NORRIS
• 金额: $ 54.41万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054200
• 关键词: 3-Dimensional; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-Protein; Atherosclerosis; Autopsy; Bacterial Infections; Binding; Biochemical; Biochemistry; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Brain; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Coagulation Process; Cognitive; Collagen; Deposition; Disease; Factor XIII; Fibrin; Fibrinogen; Functional disorder; Genetic; Hemostatic function; Human; Image; Imaging Techniques; Immunohistochemistry; Inflammation; Inflammatory; Lead; Magnetic Resonance Imaging; Microfluidics; Mouse Strains; Multiple Sclerosis; Mus; Muscular Dystrophies; Mutation; Nerve Degeneration; Neurons; Nutrient; Oxygen; Pathogenesis; Pathologic; Pathology; Peptides; Plasma; Plasmin; Play; Proteins; Resistance; Rheumatoid Arthritis; Role; Sampling; Spin Labels; Spinal cord injury; Stroke; Structural defect; Structure; Surface; Transglutaminases; abeta accumulation; abeta deposition; cell injury; cerebrovascular pathology; cognitive ability; cognitive function; crosslink; deprivation; imaging genetics; insight; mouse model; mutant; neurological pathology; neuron loss; novel diagnostics; novel therapeutics; peripheral nerve regeneration; real-time images

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.

项目总结 纤维蛋白是血栓的主要蛋白质成分，对正常止血至关重要。它也很好地- 确定除了其有益的功能外，过量或持久的纤维蛋白可导致或加剧 多种病理情况，包括动脉粥样硬化、类风湿性关节炎、中风、脊髓损伤、多发性 硬化症、肌营养不良、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)的多肽，与纤维蛋白原高度亲和力结合。结果就是这样 相互作用，Aβ诱导的纤维蛋白凝块具有异常的结构和抵抗降解。持续性纤维蛋白原在 脑血管和/或脑实质会对神经功能有害。因此，我们建议 目的：探讨纤维蛋白在AD发病机制中的作用。 我们发现，降低阿尔茨海默病小鼠模型中的纤维蛋白原水平会导致病理学的减轻和改善 认知能力。然而，纤维蛋白加速神经元退化的机制仍然存在。 未知。存在两种可能的可能性：1)阻塞--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 氧气和营养物质；2)炎症-纤维蛋白沉积导致慢性炎症状态，导致 细胞损伤。 这一应用的中心假设是持续性的、结构异常的纤维蛋白凝块形成于 Aβ的存在有助于观察到AD的炎症和神经变性。我们将研究 纤维蛋白在AD患者和小鼠AD发病机制中作用的体外凝血试验、遗传学和成像研究 小鼠模型，并对人体样本进行生化分析。这些研究可能会为新的 AD患者的诊断和治疗。