2018 — 2021 |
Norris, Erin H Strickland, Sidney [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Fibrinogen in Alzheimer's Disease
PROJECT SUMMARY Fibrin is the major protein component of blood clots and is critical for normal hemostasis. It is also well- established that in addition to its beneficial function, excessive or persistent fibrin can lead to or exacerbate many pathological conditions, including atherosclerosis, rheumatoid arthritis, stroke, spinal cord injury, multiple sclerosis, muscular dystrophy, peripheral nerve regeneration, and even bacterial infection. Beta-amyloid (A?), a peptide that contributes to Alzheimer?s disease (AD), binds to fibrinogen with high affinity. As a result of this interaction, A?-induced fibrin clots have an abnormal structure and resist degradation. Persistent fibrin in the brain?s blood vessels and/or the parenchyma would be deleterious to neuronal function. We therefore propose to investigate how fibrin affects the pathogenesis of AD. We have found that reducing fibrinogen levels in AD mouse models results in reduced pathology and better cognitive ability. However, the mechanism by which fibrin accelerates neuronal degeneration remains unknown. Two likely possibilities exist: 1) Occlusion ? fibrin clots are deposited in the vascular and perivascular space, resulting in reduced blood flow, increased A? accumulation, and neuronal damage due to deprivation of oxygen and nutrients; and 2) Inflammation ? fibrin deposits drive a chronic inflammatory state that leads to cellular damage. The central hypothesis of this application is that the persistent, structurally abnormal fibrin clots formed in the presence of A? contribute to the inflammation and neurodegeneration observed in AD. We will examine the effects of fibrin on AD pathogenesis in AD patients and mice using ex vivo clotting assays, genetics/imaging in a mouse model, and biochemical analysis of human samples. These studies may provide insights for new diagnostics and therapies for AD patients.
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0.943 |
2018 — 2021 |
Norris, Erin H Strickland, Sidney [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of the Contact System in Alzheimer's Disease
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 (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.
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0.943 |