Role of the Contact System in Alzheimer's Disease

接触系统在阿尔茨海默病中的作用

基本信息

批准号：
10112965
负责人：
ERIN H NORRIS
金额：
$ 54.63万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112965
关键词：
Abbreviations Activated Partial Thromboplastin Time measurement Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid beta-Protein Antisense Oligonucleotides Biochemical Biological Assay Blood Coagulation Factor Blood coagulation Bradykinin Brain Pathology Cleaved cell Clinical Coagulation Process Cognition Cognition Disorders Complex Control Groups Disease Disease Progression Drug Targeting FDA approved Functional disorder Future Genes Hemostatic function High-Molecular-Weight Kininogen Human Hypertension Image Impaired cognition Inflammation Inflammatory Kininogens Knock-out Link Measures Molecular Molecular Weight Mus Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Phenotype Plasma Plasma Kallikrein Prostate-Specific Antigen Reading Reporting Role Sampling Scheme Subgroup System Techniques arm cognitive function effective therapy experimental study familial Alzheimer disease improved inhibitor/antagonist insight knock-down mouse model neuron loss novel strategies novel therapeutic intervention patient stratification personalized medicine targeted treatment therapy design thrombotic vascular abnormality vascular inflammation

项目摘要

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.

项目摘要除了神经元变性外，许多阿尔茨海默氏病（AD）患者患有血管异常和炎症。接触激活系统可能有助于这两种病理由于它可以引发亲栓性和促炎的途径。我们已经证明了接触与对照组相比，AD患者和AD小鼠模型中的系统被显着激活。这 β-淀粉样蛋白肽（Aβ）是AD病理学的驱动因素，可以激活因子12（F12），这是接触的引发剂系统。我们最近表明，F12的耗竭可以在早期的早期阶段改善AD小鼠的病理疾病。这些结果表明，超过接触系统激活可能会促进AD病理和认知衰退。没有有效的AD治疗方法。 F12激活与AD发病机理之间的联系提供了可能的新方法治疗方法。接触系统是广告疗法的有吸引力的目标。人类 F12和小鼠缺乏敲除不同接触系统途径基因的止血性正常。如果 F12的激活确实在AD病理学中删除，旨在阻止接触系统的疗法可能疾病进展缓慢，而不会影响正常止血。那，我们的研究可能揭示了新的目标抑制对AD进展的血栓形成和炎症贡献。积极的结果可能能够由于已经存在针对接触系统的FDA批准药物，因此可以迅速应用于AD患者。