Anti-high molecular weight kininogen antibody for Alzheimer's disease diagnosis and therapy

用于阿尔茨海默病诊断和治疗的抗高分子量激肽原抗体

• 批准号: 10097427
• 负责人: ERIN H NORRIS
• 金额: $ 175.09万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097427
• 关键词: Abbreviations; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Antibodies; Antisense Oligonucleotides; Biological Assay; Blocking Antibodies; Blood; Blood Coagulation Factor; Blood Vessels; Blood coagulation; Bradykinin; Brain; Cerebral hemisphere hemorrhage; Cleaved cell; Clinical; Coagulation Process; Complex; Detection; Diagnostic; Diagnostic tests; Enzyme-Linked Immunosorbent Assay; Factor XI; Factor XII; Generations; Goals; Hemorrhage; High-Molecular-Weight Kininogen; Human; Individual; Inflammation; Inflammatory; Kininogens; Lead; Modeling; Molecular Weight; Monoclonal Antibodies; Mus; Neurobehavioral Manifestations; Neurodegenerative Disorders; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Plasma; Plasma Kallikrein; Prostate-Specific Antigen; Proteins; Research; Role; Sampling; Scheme; System; Testing; Therapeutic; Therapeutic Uses; Vascular Diseases; Vascular System; arm; effective therapy; in vivo; inhibiting antibody; interdisciplinary approach; knock-down; mouse model; neuroinflammation; non-demented; prevent; protein activation

PROJECT SUMMARY Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple pathologies, such as proteinaceous brain inclusions and neuroinflammation. The vascular system is also recognized as a factor in AD, yet there are few models to study the mechanism. We and others have found that the Aβ peptide, a known driver of AD, can activate the plasma contact system, which can lead to blood clot formation and inflammation via generation of bradykinin upon cleavage of high molecular weight kininogen (HK). There are three main lines of evidence that the contact system is involved in AD pathology: 1) Aβ activates factor XII (F12), which initiates the contact system; 2) AD patient plasma has increased contact system activation compared to that of age-matched, non-demented individuals; and 3) Knockdown of the contact system using an anti-F12 antisense oligonucleotide ameliorates AD pathology in a mouse model. HK circulates in blood as a complex with other coagulation factors, and it serves as a non-enzymatic co-factor for the activation of these proteins. Compared to other components of the contact system, depletion of HK offers more robust protection from blood clotting and inflammation due to its central role in both pathways. We have generated antibodies that are specific for cleaved HK that could help identify AD patients with contact system involvement. We also have developed antibodies that block HK cleavage, which might be beneficial to patients as they might ameliorate some of the pathologies of AD. It is important to note that people who lack a contact system are not prone to bleeding, and therefore, blocking this system in AD patients would not risk intracerebral hemorrhage. Despite decades of research, there are no effective treatments that slow or prevent AD. Progress in treating AD requires a multidisciplinary approach. We hypothesize that blocking the contact system could reduce vascular and inflammatory pathologies in AD patients. We propose to further develop our anti-HK antibodies for AD patient diagnostic and therapeutic use.

项目摘要 阿尔茨海默氏病（AD）是一种复杂的神经退行性疾病，具有多种病理，例如 蛋白质脑包含和神经炎症。血管系统也被认为是 AD中的因素，但是很少有模型可以研究该机制。我们和其他人发现Aβ 肽是AD的已知驱动器，可以激活血浆接触系统，这可能导致血液克隆 高分子量裂解时通过缓激肽产生的形成和炎症 动力学（HK）。有三个主要证据表明接触系​​统参与了广告 病理：1）Aβ激活了XII因子（F12），该因子启动了接触系统； 2）广告患者血浆 与年龄匹配的非痴呆个体相比，接触系统的激活增加了； 3）使用抗F12反义寡核苷酸改善AD的接触系统敲低接触系统 鼠标模型中的病理学。血液中的HK圆与其他凝结因子的复合物，并且 它是这些蛋白质激活的非酶辅助因素。与其他相比 接触系统的组件，香港部署可为血液服装提供更强大的保护 和由于其在这两种途径中的核心作用而引起的炎症。 我们已经产生了针对清除的HK的抗体，可以帮助识别AD患者 与接触系统的参与。我们还开发了阻塞香港裂解的抗体， 可能对患者有益，因为他们可以改善AD的某些病理。这很重要 要注意，缺乏接触系统的人不容易出血，因此阻止了这一点 AD患者的系统不会风险脑出血。 尽管进行了数十年的研究，但仍没有有效的治疗方法可以减慢或阻止AD。进步 治疗广告需要一种多学科的方法。我们假设阻止接触系统 可以减少AD患者的血管和炎症性病理。我们建议进一步发展 我们用于AD患者诊断和治疗用途的抗HK抗体。