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.

项目总结 阿尔茨海默病(AD)是一种复杂的神经退行性疾病，具有多种病理机制，如 蛋白质脑内含物和神经炎症。血管系统也被认为是一种 阿尔茨海默病的致病因素，但目前研究其发病机制的模型很少。我们和其他人发现Aβ 已知的阿尔茨海默病的驱动因素是多肽，它可以激活血浆接触系统，从而导致血栓 大分子裂解时产生缓激肽的形成和炎症 激肽原(香港)。有三条主要证据表明联系系统与AD有关 病理：1)β激活F12因子，启动接触系统；2)AD患者血浆 与年龄匹配的非痴呆者相比，接触系统的激活程度更高； 和3)使用抗F12反义寡核苷酸击倒接触系统以改善AD 小鼠模型中的病理学。HK作为与其他凝血因子的复合体在血液中循环，以及 它是激活这些蛋白质的非酶辅助因子。与其他 接触系统的组成部分，耗尽HK提供更强大的防止血液凝结的保护 以及炎症，因为它在这两个途径中都起着核心作用。 我们已经产生了针对裂解HK的抗体，可以帮助识别AD患者 有联系系统参与的。我们还开发了阻断HK裂解的抗体，这 可能对患者有益，因为他们可能会改善AD的一些病理情况。这很重要 要注意，缺乏接触系统的人不容易出血，因此，阻止这一点 AD患者的系统不会有脑内出血的风险。 尽管几十年的研究，没有有效的治疗方法来减缓或预防阿尔茨海默病。取得的进展 治疗阿尔茨海默病需要多学科的方法。我们假设封锁联络系统 可以减轻AD患者的血管和炎性病变。我们建议进一步发展 我们的抗香港抗体可用于AD患者的诊断和治疗。