Alzheimer's disease (AD) is a neurodegenerative disorder that leads to profound cognitive decline and eventually death. There are no effective treatments or preventative measures available, and the incidence and prevalence of the disease are increasing. New insights and tractable therapeutic targets are sorely needed. Genetic evidence indicates that a major cause of AD is the production of the ?-amyloid (A?) peptide. The A? 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. We have demonstrated an increase in blood brain barrier (BBB) permeability and neurovascular damage in AD mice, and we showed that fibrin(ogen) deposition potentiates these processes. We have also found that A binds to fibrinogen and has a dramatic effect on fibrin clot formation. Clots formed in the presence of A? have an abnormal structure and are resistant to degradation by fibrinolytic enzymes. Therefore, in the presence of A?, any fibrin deposits formed would be more persistent and would 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 ApoE affects the interaction between fibrinogen and A? and the isoforms differentially influence fibrinogen deposition in the human brain. To further study the role of A? in fibrin clot formation, we will combine in vitro and in vivo techniques to analyze and characterize the interaction between A? and fibrinogen. The role of the various ApoE isoforms in this process will also be examined. Finally, we will examine the effects of fibrinogen deposition on the brain in the absence of A? to deduce the specific contribution of fibrin(ogen) to AD-related pathologies. The proposed experiments will define the role of fibrin(ogen) in AD and could lead to new therapeutic strategies for preventing or retarding progression of the disease.

National Institute of Health (NIH)
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Hemostasis and Thrombosis Study Section (HT)
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Corriveau, Roderick A
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Rockefeller University
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New York
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Yao, Yao; Norris, Erin H; Strickland, Sidney (2015) The cellular origin of laminin determines its role in blood pressure regulation. Cell Mol Life Sci 72:999-1008
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Zamolodchikov, Daria; Strickland, Sidney (2012) A? delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin. Blood 119:3342-51
Cortes-Canteli, Marta; Paul, Justin; Norris, Erin H et al. (2010) Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease. Neuron 66:695-709
Cortes-Canteli, M; Strickland, S (2009) Fibrinogen, a possible key player in Alzheimer's disease. J Thromb Haemost 7 Suppl 1:146-50

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