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: 8108431
• 负责人: SIDNEY STRICKLAND
• 金额: $ 52.48万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-25 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108431
• 关键词: Affect; Alleles; Alzheimer' s Disease; Amyloid; Apolipoprotein E; Binding; Binding Sites; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Brain; Cell Death; Cerebrum; Cessation of life; Coagulation Process; Cognition; Data; Deposition; Disease; Disease Progression; Electron Microscopy; Enzymes; Fibrin; Fibrinogen; Genes; Genetic; Genotype; Hemostatic function; Human; Impaired cognition; In Vitro; Incidence; Late Onset Alzheimer Disease; Lead; Measures; Mus; Nature; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Patients; Peptides; Permeability; Pharmacia brand of estropipate; Plasminogen; Play; Population; Prevalence; Process; Production; Protein Isoforms; Reporting; Resistance; Role; Severity of illness; Structure; Techniques; X-Ray Crystallography; base; brain tissue; cerebral hypoperfusion; effective therapy; extracellular; genetic risk factor; in vivo; insight; mouse model; neuroinflammation; novel therapeutics; prevent; research study; therapeutic target

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that leads to profound cognitive decline and eventually death. There are no effective treatments or preventative measures available, and the incidence and prevalence of the disease are increasing. New insights and tractable therapeutic targets are sorely needed. Genetic evidence indicates that a major cause of AD is the production of the ¿-amyloid (A¿) peptide. The A¿ peptide can oligomerize and be deposited as extracellular plaques in the brain and blood vessels, but the mechanism of how it leads to neuronal death is not known. There is increasing evidence of a vascular contribution in AD: patients suffer from brain hypoperfusion, the cerebral vasculature is damaged, and abnormal hemostasis is present. Circulatory deficiencies could therefore play an important role in the pathogenesis of this disease. We have demonstrated an increase in blood brain barrier (BBB) permeability and neurovascular damage in AD mice, and we showed that fibrin(ogen) deposition potentiates these processes. We have also found that A binds to fibrinogen and has a dramatic effect on fibrin clot formation. Clots formed in the presence of A¿ have an abnormal structure and are resistant to degradation by fibrinolytic enzymes. Therefore, in the presence of A¿, any fibrin deposits formed would be more persistent and would exacerbate BBB damage, neuroinflammation, and neuronal death. In keeping with the known genetic interaction between AD and the ApoE genotype, we have also demonstrated that ApoE affects the interaction between fibrinogen and A¿ and the isoforms differentially influence fibrinogen deposition in the human brain. To further study the role of A¿ in fibrin clot formation, we will combine in vitro and in vivo techniques to analyze and characterize the interaction between A¿ and fibrinogen. The role of the various ApoE isoforms in this process will also be examined. Finally, we will examine the effects of fibrinogen deposition on the brain in the absence of A¿ to deduce the specific contribution of fibrin(ogen) to AD-related pathologies. The proposed experiments will define the role of fibrin(ogen) in AD and could lead to new therapeutic strategies for preventing or retarding progression of the disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) affects a large and growing portion of the population and has been studied for over a century, yet there are few available therapies to aid in the loss of cognition and no effective preventative measures. We have found that the buildup of fibrin in the brains of AD mouse models is deleterious and contributes to their cognitive decline. The proposed studies will provide a new way to understand how this disease progresses from the perspective of disrupted blood flow to the brain, which will also explain how the nature of the fibrin clot is altered in the presence of ¿-amyloid to allow for this persistence and how other genes can influence progression.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种神经退行性疾病，导致认知能力下降，最终导致死亡。没有有效的治疗方法或预防措施，疾病的事件和患病率正在增加。迫切需要新的见解和可进行的治疗目标。遗传证据表明，AD的主要原因是 - 淀粉样蛋白（a。）肽的产生。肽可以将肽寡聚并沉积为脑和血管中的细胞外斑块，但是尚不清楚它如何导致神经元死亡的机理。越来越多的证据表明AD的血管贡献：患者患有脑部缺血，脑血管受损，并提出异常止血。因此，循环缺陷可能在该疾病的发病机理中起重要作用。我们已经证明了AD小鼠的血液脑屏障（BBB）渗透性和神经血管损伤的增加，我们表明纤维蛋白（OGEN）沉积电位这些过程。我们还发现，A与纤维蛋白原结合，对纤维蛋白血块的形成具有巨大的作用。在存在A的存在下形成的凝块具有异常结构，并且纤维蛋白水解酶耐降解。因此，在存在a的情况下，形成的任何纤维蛋白沉积物都将更加持久，并且会加剧BBB损害，神经炎症和神经元死亡。为了与AD和APOE基因型之间的已知遗传相互作用保持一致，我们还证明APOE会影响纤维蛋白原与A之间的相互作用，而同工型对人脑中的纤维蛋白原沉积有所不同。为了进一步研究A检测在纤维蛋白凝块形成中的作用，我们将在体外和体内技术结合分析和表征A a和纤维蛋白原之间的相互作用。还将检查各种APOE同工型在此过程中的作用。最后，我们将在没有A的情况下检查纤维蛋白原沉积对大脑的影响，以推断纤维蛋白（OGEN）对与AD相关的病理的特定贡献。提出的实验将定义纤维蛋白（OGEN）在AD中的作用，并可能导致预防或阻碍疾病进展的新的治疗策略。 公共卫生相关性：阿尔茨海默氏病（AD）影响了大量且不断增长的人口，并且已经研究了一个多世纪，但是几乎没有可用的疗法可以帮助丧失认知和没有有效的预防措施。我们发现，AD鼠标模型的大脑中纤维蛋白的积聚是有害的，并有助于其认知能力下降。拟议的研究将提供一种新的方法来了解该疾病从流向大脑的血液流动的角度如何发展，这也将解释纤维蛋白血块的性质如何在存在的存在 - 淀粉样蛋白的存在下改变这种持久性以及其他基因如何影响进展。