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（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，可导致严重的认知能力下降并最终死亡。没有有效的治疗或预防措施，这种疾病的发病率和流行率正在上升。迫切需要新的见解和易于处理的治疗目标。遗传学证据表明，AD的一个主要原因是淀粉样蛋白（A）肽的产生。A肽可以寡聚化并作为细胞外斑块沉积在脑和血管中，但其如何导致神经元死亡的机制尚不清楚。有越来越多的证据表明血管在AD中起作用：患者患有脑灌注不足，脑血管受损，并且存在异常止血。因此，循环缺陷可能在这种疾病的发病机制中发挥重要作用。我们已经证明了AD小鼠血脑屏障（BBB）通透性和神经血管损伤的增加，我们发现纤维蛋白（原）沉积增强了这些过程。我们还发现A与纤维蛋白原结合，对纤维蛋白凝块形成有显著影响。在A？存在下形成的凝块具有异常结构，并且对纤维蛋白溶解酶的降解具有抗性。因此，在A？存在的情况下，形成的任何纤维蛋白沉积物将更加持久，并将加剧BBB损伤、神经炎症和神经元死亡。与AD和ApoE基因型之间已知的遗传相互作用一致，我们还证明了ApoE影响纤维蛋白原和A？之间的相互作用，并且同种型差异地影响纤维蛋白原在人脑中的沉积。为了进一步研究A <$在纤维蛋白凝块形成中的作用，我们将联合收割机体外和体内技术来分析和表征A <$和纤维蛋白原之间的相互作用。各种载脂蛋白E亚型在这一过程中的作用也将进行检查。最后，我们将研究在缺乏A的情况下纤维蛋白原沉积对大脑的影响，以推断纤维蛋白（原）对AD相关病理的具体贡献。拟议的实验将确定纤维蛋白（原）在AD中的作用，并可能导致预防或延缓疾病进展的新治疗策略。 公共卫生关系：阿尔茨海默氏病（AD）影响大部分且不断增长的人群，并且已经被研究了超过世纪，然而几乎没有可用的疗法来帮助认知丧失，并且没有有效的预防措施。我们已经发现，AD小鼠模型脑中纤维蛋白的积累是有害的，并导致其认知能力下降。拟议的研究将提供一种新的方法来了解这种疾病是如何从血液流向大脑的角度发展的，这也将解释纤维蛋白凝块的性质如何在淀粉样蛋白存在的情况下改变以允许这种持久性以及其他基因如何影响进展。