Alzheimer's disease (AD) is a neurodegenerative disorder that leads to profound cognitive decline and eventually death. There are no effective long- term treatments or preventative measures available, and the prevalence of the disease is increasing. New insights and therapeutic targets are sorely needed. Genetic evidence indicates that a major cause of AD is the production of the amyloid-[unreadable] (A[unreadable]) peptide, which is proteolytically derived from the amyloid-b precursor protein. The A[unreadable] peptide can oligomerize and be deposited as extracellular plaques in the brain and blood vessels, but the mechanism of how it leads to neuronal death is not known. There is increasing evidence of a vascular contribution in AD: patients suffer from brain hypoperfusion, the cerebral vasculature is damaged, and abnormal hemostasis is present. Circulatory deficiencies could therefore play an important role in the pathogenesis of this disease. During the last grant period, we demonstrated an increase in blood brain barrier (BBB) permeability and neurovascular damage in AD mice, and we showed that fibrin deposition potentiates these processes. We have now found that A[unreadable] binds to fibrinogen and has a dramatic effect on fibrin clot formation. Clots formed in the presence of A[unreadable] have an abnormal structure and are resistant to degradation by fibrinolytic enzymes. Therefore, in the presence of A[unreadable], any fibrin clots formed would be more persistent and exacerbate BBB damage, neuroinflammation, and neuronal death. In keeping with the known genetic interaction between AD and the ApoE genotype, we have also demonstrated that the different ApoE isoforms differentially affect the fibrinogen/Ab interaction and the structure of the fibrin clot formed. To further study the role of A[unreadable] in fibrin clot formation, we will combine in vitro and in vivo techniques to analyze and characterize the interaction between A[unreadable] and fibrin(ogen). The role of the various ApoE isoforms in this process will be also examined. The proposed experiments will define the role of fibrin(ogen) in AD and possibly lead to new therapeutic strategies for preventing or retarding progression of the disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) affects a large and growing portion of the population and has been studied for over a century, yet there are few available therapies to aid in the loss of cognition and no effective preventative measures. We have found that the build-up of fibrin in the brains of AD mouse models is deleterious and contributes to their cognitive decline. The proposed studies will provide a new way to understand how this disease progresses from the perspective of disrupted blood flow to the brain, which will also explain how the nature of the fibrin clot is altered in the presence of amyloid-[unreadable] to allow for this persistence and how other genes can influence progression.