Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 46, Pages 22921-22923Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1914831116
Keywords
Alzheimer's disease; bradykinin; beta-amyloid; high molecular weight kininogen
Categories
Funding
- NIH [NS102721]
- Cure Alzheimer's Fund
- Alzheimer's Association
- Robertson Therapeutic Development Fund
- Rudin Family Foundation
- NIH National Center for Advancing Translational Sciences Grant through Rockefeller University [UL1TR001866]
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Bradykinin is a proinflammatory factor that mediates angioedema and inflammation in many diseases. It is a key player in some types of hereditary angioedema and is involved in septic shock, traumatic injury, Alzheimer's disease (AD), and stroke, among others. Activation of the plasma contact system leads to elevated levels of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to release bradykinin. Drug development for bradykinin-meditated pathologies has focused on designing inhibitors to the enzymes that cleave HK (to prevent bradykinin release) or antagonists of endothelial bradykinin receptors (to prevent down-stream bradykinin action). Here we show a strategy to block bradykinin generation by using an HK antibody that binds to HK, preventing its cleavage and subsequent bradykinin release. We show that this antibody blocks dextran sodium sulfate-induced HK cleavage and bradykinin production. Moreover, while the pathogenic AD peptide beta-amyloid (A beta)42 cleaves HK and induces a dramatic increase in bradykinin production, our HK antibody blocked these events from occurring. These results may provide strategies for developing treatments for bradykinin-driven pathologies.
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