Role of Fibrinogen in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是一种神经退行性疾病，会导致严重的认知能力下降，最终导致死亡。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增加。迫切需要新的见解和易于处理的治疗目标。遗传证据表明，阿尔茨海默病的一个主要原因是淀粉样蛋白(A)肽的产生。A？肽可以寡聚并以细胞外斑块的形式沉积在大脑和血管中，但它如何导致神经元死亡的机制尚不清楚。越来越多的证据表明阿尔茨海默病与血管有关：患者患有脑低灌注症，脑血管受损，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)通透性的增加和神经血管的损伤，我们还证明了纤维蛋白(原)的沉积加强了这些过程。我们还发现，A与纤维蛋白原结合，对纤维蛋白凝块的形成有显著影响。在A的存在下形成的凝块具有异常的结构，并能抵抗纤溶酶的降解。因此，在A‘存在的情况下，形成的任何纤维蛋白沉淀物都会更持久，并会加剧BBB损伤、神经炎症和神经元死亡。为了与已知的AD和ApoE基因之间的遗传相互作用保持一致，我们还证明了ApoE影响纤维蛋白原和Aβ之间的相互作用，并且不同的亚型对纤维蛋白原在人脑中的沉积有不同的影响。为了进一步研究A？纤维蛋白凝块形成的作用，我们将结合体外和体内技术来分析和表征A？与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被研究。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)在阿尔茨海默病中的作用，并可能导致预防或延缓疾病进展的新治疗策略。 公共卫生相关性：阿尔茨海默病(AD)影响着很大一部分人口，而且还在不断增长，人们已经研究了一个多世纪，但几乎没有可用的治疗方法来帮助认知丧失，也没有有效的预防措施。我们发现，阿尔茨海默病模型小鼠大脑中纤维蛋白的积聚是有害的，并导致他们的认知能力下降。拟议的研究将提供一种新的方法，从流向大脑的血流中断的角度来理解这种疾病是如何进展的，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。

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.