Role of the Contact System in Alzheimer's Disease

项目总结 除了神经元变性外，许多阿尔茨海默病(AD)患者还患有血管疾病 异常和发炎。接触激活系统可能对这两种病理起作用。 因为它既可以启动血栓形成途径，也可以启动炎症途径。我们已经证明了联系人 与对照组相比，阿尔茨海默病患者和AD小鼠模型中系统的激活程度显著增加。这个 AD病理的驱动力--β-淀粉样蛋白(A-β)可以激活接触的起始者因子12(F12) 系统。我们最近发现，F12的缺失可以改善AD小鼠早期的病理改变。 疾病。这些结果表明，过度的接触系统激活可能促进AD的病理和认知 拒绝。 目前尚无治疗阿尔茨海默病的有效方法。F12激活与AD发病机制之间的联系提供了一种 可能的新治疗方法。接触系统是AD治疗的一个有吸引力的目标；人类 F12缺陷和不同接触系统途径基因敲除的小鼠止血正常。如果 F12的激活在AD病理中确实是有害的，旨在阻断接触系统的治疗可能 延缓疾病进展，同时不影响正常止血。因此，我们的研究可能会揭示新的目标 抑制血栓和炎症在AD进展中的作用。积极的结果或许能够 快速应用于AD患者，因为FDA批准的针对接触系统的药物已经存在。

PROJECT SUMMARY In addition to neuronal degeneration, many Alzheimer’s disease (AD) patients suffer from vascular abnormalities and inflammation. The contact activation system may contribute to both of these pathologies since it can launch both pro-thrombotic and pro-inflammatory pathways. We have shown that the contact system is significantly more activated in AD patients and AD mouse models compared to control groups. The beta-amyloid peptide (Aβ), a driver of AD pathology, can activate Factor 12 (F12), the initiator of the contact system. We have recently shown that depletion of F12 ameliorates pathology in AD mice at early stages of disease. These results indicate that excess contact system activation may promote AD pathology and cognitive decline. There is no effective treatment for AD. A link between F12 activation and the pathogenesis of AD provides a possible novel approach to treatment. The contact system is an attractive target for AD therapy; humans deficient in F12 and mice with knockout of different contact system pathway genes have normal hemostasis. If F12 activation is indeed deleterious in AD pathology, therapies designed to block the contact system might slow disease progression while not affecting normal hemostasis. Thus, our studies may reveal new targets to suppress both thrombotic and inflammatory contributions to AD progression. Positive results might be able to be applied to AD patients rapidly as already FDA-approved drugs targeting the contact system already exist.