A New Role for Beta-Amyloid in Alzheimer's Disease: Initiation of Thrombotic and Inflammatory Processes Via Coagulation Factor XII and Fibrinogen

Author

Daria Zamolodchikov

Date of Award

2015

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Strickland Laboratory

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no effective therapies. While abundant genetic, histological, and experimental evidence links the beta-amyloid (Aβ) peptide to disease onset and progression, the mechanisms behind neuronal dysfunction in AD are not completely understood. It is now clear that AD is a complex, multifactorial disease characterized by vascular dysfunction, prothrombotic state, and inflammation, but whether these conditions are a cause or consequence of disease is debated. Prothrombotic and inflammatory states can contribute to alterations in cerebral blood flow resulting in hypoperfusion. Since neuronal function is dependent on an uninterrupted blood supply sustained by a healthy vasculature, agents capable of eliciting thrombosis and/or inflammation could play a key role in AD onset and progression. The contact activation system, initiated by activation of the plasma protein FXII, is capable of launching both thrombotic and inflammatory pathways. I investigated whether Aβ could directly induce these pathways by interacting with FXII in vitro, in AD mouse models, and in AD patients. A prothrombotic state may also result from reduced clot degradation, as seen in mouse models of AD. I therefore investigated the mechanism by which clots formed in the presence of Aβ are structurally altered and resistant to degradation. I established the ability of Aβ to initiate prothrombotic and inflammatory processes via activation of the FXII-driven contact system, and provided evidence for these processes in AD patients and mouse models. I also defined the regions involved in Aβ-fibrinogen binding and elucidated the mechanism by which this interaction results in delayed fibrinolysis. My results suggest new pathogenic mechanisms, diagnostic tests, and therapeutic targets for AD.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Recommended Citation

Zamolodchikov, Daria, "A New Role for Beta-Amyloid in Alzheimer's Disease: Initiation of Thrombotic and Inflammatory Processes Via Coagulation Factor XII and Fibrinogen" (2015). Student Theses and Dissertations. 284.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/284