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 (Aβ), a peptide that contributes to Alzheimer’s disease (AD), binds to fibrinogen with high affinity. As a result of this interaction, Aβ-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 Aβ 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 Aβ 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.

PROJECT NARRATIVE Perturbations in blood clotting and inflammation are present in many Alzheimer’s disease (AD) patients and mouse models. We will use genetic, biochemical, and state-of-the-art imaging techniques to help clarify the contributions of fibrin, the major blood clotting protein, in AD pathology to pave the way for new diagnostics and therapies for human AD patients.