Date of Award
Doctor of Philosophy (PhD)
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.
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.