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Alzheimer's Disease Research - Current Award

Dr. Marta Cortes-Canteli

Marta Cortes-Canteli, Ph.D.

Rockefeller University
New York, NY

Title: Role Of Amyloid Beta-Fibrinogen Interaction In Alzheimer's Disease
Non-Technical Title: Blood Clots In The Alzheimer's Disease Brain

Mentor:
Sidney Strickland, Ph.D.
Rockefeller University

Duration: April 1, 2009 - March 31, 2011
Award Type: Research Fellowship
Award Amount: $100,000


Summary:

Amyloid beta interacts with fibrinogen in test tubes and prevents fibrin clots from degrading. Studying this phenomenon in living systems in addition to the role of ApoE in disease pathology will help to clarify the role of fibrin in the abnormal cerebral vasculature in Alzheimer's disease.

Details:


Alzheimer's disease is a complex disorder in which many biological factors are implicated. Despite all the research and investment efforts, the lack of a defined pathological mechanism in this disease has impeded development of an effective treatment as there are only five drugs currently approved, which have minor effects on disease progression. Therefore, new approaches are needed urgently. A large body of research implicates blood circulation as a contributing factor in Alzheimer's disease, as patients have decreased and damaged blood circulation in their brains. Also, epidemiological studies have demonstrated that the greater number of vascular risk factors, the higher the probability of suffering from this disease. The protein fibrin, the major component of the blood clots, could play an important role in the vascular component of Alzheimer's disease. We know that fibrin associates with the peptide amyloid beta, whose levels are increased in Alzheimer's disease, making fibrin clots difficult to destroy. These persistent clots could lead to vascular deficiencies and decreased blood flow, increased inflammation, and neuronal death, all of which are features present in Alzheimer's disease patients. Thus, this interaction between fibrin and amyloid beta may play a role in the pathogenesis of this disease. To explore this hypothesis, this project will involve the following experiments:

1)Study the association between fibrin and amyloid beta in Alzheimer's disease mouse models and Alzheimer's disease human post-mortem brain tissue;

2)Characterize the living system blood clot formation and degradation in Alzheimer's disease mice;

3) Examine the effect of ApoE isoforms, a genetic risk factor for this disease, on clot formation and in the fibrinogen-amyloid beta interaction.

Our hypothesis is that fibrin deposits in the brain's blood vessels of Alzheimer's patients, forming clots in which amyloid beta intercalates and blocks their degradation. This event in turn reduces cerebral blood flow and leads to the development of Alzheimer's disease. These studies will help to understand the role of fibrin deposits in the abnormal cerebral vasculature in this disease. Identification of the amyloid beta-fibrinogen interaction as a new target may lead to new therapeutic strategies for preventing or retarding progression of Alzheimer's disease.

Publications:

Cortes-Canteli M, Paul J, Norris EH, Bronstein R, Ahn HJ, Zamolodchikov D, Bhuvanendran S, Fenz KM, Strickland S. Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease. Neuron. 2010 Jun 10;66(5):695-709. PubMed Icon Google Scholar Icon

Progress Updates:

Alzheimer's disease (AD) is a complex disorder in which many biological factors are implicated. New therapeutic approaches are needed since there currently is no effective treatment available. Blood circulation has been considered a contributing factor in Alzheimer's disease, and epidemiological studies have demonstrated that the greater number of vascular risk factors, the higher the probability of developing AD. Fibrin, the major protein component of blood clots, may play an important role in the blood-vessel component of AD. Previous studies demonstrated that fibrin associates with the Abeta peptide in the brain of AD mice. Now, we have seen that this association is taking place in the brain's blood vessels of AD patients. Also, we had previously seen in lab “test tubes” that Abeta alters fibrin clot structure and makes the clot difficult to degrade. Now, we have analyzed whether this occurs in animals as well by provoking clots in the brain of live mice. We have found that blood vessels of AD mice clogged with clots faster than normal mice and that these clots persisted longer.

Our hypothesis is that fibrin deposits and forms clots in the brain's blood vessels of Alzheimer's patients, where the presence of Abeta will block their degradation. This event, in turn, reduces cerebral blood flow and leads to AD pathogenesis. Identification of the Abeta-fibrinogen interaction as a novel target may lead to new therapeutic strategies for preventing or slowing progression of Alzheimer's disease.