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: 10297855
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297855
• 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; Spinal cord injury; Stroke; Structural defect; Structure; Surface; Transglutaminases; abeta accumulation; abeta deposition; arterial spin labeling; 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.

项目摘要 纤维蛋白是血凝块的主要蛋白质成分，对于正常止血至关重要。也很好 确定除了其有益功能外，过量或持续的纤维蛋白还会导致或加剧 许多病理状况，包括动脉粥样硬化，类风湿关节炎，中风，脊髓损伤，多个 硬化，肌肉营养不良，周围神经再生甚至细菌感染。 β-淀粉样蛋白（Aβ）， 有助于阿尔茨海默氏病（AD）的肽与具有高亲和力的纤维蛋白原结合。结果 相互作用，Aβ诱导的纤维蛋白凝块具有异常结构并抵抗降解。持续的纤维蛋白 大脑的血管和/或副群对神经元功能有害。因此，我们建议 研究纤维蛋白如何影响AD的发病机理。 我们发现，在AD小鼠模型中降低纤维蛋白原水平会导致病理减少和更好 认知能力。但是，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）阻塞 - 纤维蛋白布沉积在血管和周围 空间，导致血流减少，Aβ积累增加以及由于剥夺而导致的神经元损害 氧气和营养； 2）炎症 - 纤维蛋白沉积驱动慢性炎症状态，导致 细胞损伤。 该应用的中心假设是在结构上形成的持续性，结构异常的纤维素布 Aβ的存在有助于AD中观察到的炎症和神经退行性。我们将检查 纤维蛋白对AD患者和小鼠AD发病机理的影响，使用体内服装分析，遗传学/成像 小鼠模型和人类样品的生化分析。这些研究可能为新的见解提供见解 广告患者的诊断和疗法。