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 (A?), 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.
Alzheimer?s disease (AD) is a fatal cognitive disorder that results in extensive neuronal cell death, which may be caused by increased blood clotting and inflammation. We have found that the contact activation system, which regulates both the clotting and inflammatory pathways, is triggered in AD patients and mouse models. Using biochemical, state-of-the-art imaging, and pharmacological techniques, we will explore the role of the contact system in AD pathophysiology.
| Suidan, Georgette L; Singh, Pradeep K; Patel-Hett, Sunita et al. (2018) Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability. Blood Adv 2:954-963 |
