Fibrin Formation and Dissolution in the Progression of Amyloid-Beta Pathology in Alzheimer's Disease

<p>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 as 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-β (Aβ) peptide, which is proteolytically derived from the amyloid-β precursor protein. The Aβ 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 found an increase in blood brain barrier (BBB) permeability and neurovascular damage in AD mice, and showed that fibrin deposition potentiates these processes. We then found that Aβ binds to fibrinogen and alters fibrin clot formation. Clots formed in the presence of Aβ have an abnormal structure and are resistant to degradation by fibrinolytic enzymes. We also found that ApoE isoforms differentially affect the structure of the fibrin clot formed in the presence of Aβ, which is consistent with the known genetic interaction between AD and the ApoE genotype. These results suggest that in the presence of Aβ, dysfunctional fibrin clots alter thrombosis and hemostasis and exacerbate the BBB damage and neuroinflammation, thus promoting the disease process in AD.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2009

Author dc:creator

• Paul, Justin

Contributors dc:contributor

• Sidney Strickland

• Alzheimer's disease (AD)
• amyloid-beta
• blood brain barrier
• fibrin clot formation
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/123

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1122