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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：
10328951
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/10328951
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 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 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 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之外，许多阿尔茨海默病（AD）患者还患有血管变性。异常和炎症。接触激活系统可能导致这两种病理因为它可以启动促血栓形成和促炎途径。我们已经证明，与对照组相比，AD患者和AD小鼠模型中系统的激活显著更多。的 β-淀粉样肽（Aβ）是AD病理学的驱动因素，可激活因子12（F12），即接触的起始因子。系统我们最近发现，F12的缺失改善了AD小鼠在早期阶段的病理学，疾病这些结果表明，过度的接触系统激活可能会促进AD的病理和认知功能，下降目前还没有有效的治疗AD的方法。F12激活与AD发病机制之间的联系提供了一个新的证据。可能的新的治疗方法。接触系统是AD治疗的一个有吸引力的靶点;人类 F12缺陷和敲除不同接触系统途径基因的小鼠具有正常止血。如果 F12激活在AD病理学中确实是有害的，设计用于阻断接触系统的疗法可能减缓疾病进展，同时不影响正常止血。因此，我们的研究可能会揭示新的靶点，抑制血栓形成和炎症对AD进展的贡献。积极的结果可能会由于已经存在FDA批准的靶向接触系统的药物，因此可以快速应用于AD患者。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo.

DOI：
10.1182/bloodadvances.2021006485
发表时间：
2023-04-11
期刊：
BLOOD ADVANCES
影响因子：
7.5
作者：
Chen, Zu-Lin;Singh, Pradeep K.;Horn, Katharina;Calvano, Marissa R.;Kaneki, Shigeru;McCrae, Keith R.;Strickland, Sidney;Norris, Erin H.
通讯作者：
Norris, Erin H.

Blocking domain 6 of high molecular weight kininogen to understand intrinsic clotting mechanisms.

DOI：
10.1002/rth2.12815
发表时间：
2022-10
期刊：
Research and practice in thrombosis and haemostasis
影响因子：
4.6
作者：
Singh PK;Chen ZL;Horn K;Norris EH
通讯作者：
Norris EH

A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer's disease.

DOI：
10.1073/pnas.2309389120
发表时间：
2023-09-05
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Chen, Zu-Lin;Singh, Pradeep K.;Calvano, Marissa;Norris, Erin H.;Strickland, Sidney
通讯作者：
Strickland, Sidney

Anti-HK antibody reveals critical roles of a 20-residue HK region for Aβ-induced plasma contact system activation.

DOI：
10.1182/bloodadvances.2021006612
发表时间：
2022-05-24
期刊：
BLOOD ADVANCES
影响因子：
7.5
作者：
Chen, Zu-Lin;Singh, Pradeep Kumar;Horn, Katharina;Strickland, Sidney;Norris, Erin H.
通讯作者：
Norris, Erin H.