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2018 Grants - Strickland
Role of the Contact System in Alzheimer's Disease
Sidney Strickland, Ph.D.
New York, New York
2018 Zenith Fellows Award (ZEN)
How can a process linked to blood clotting and inflammation promote the onset of Alzheimer's disease?
Studies have found that when the cerebrovascular system (which controls blood flow in the brain) becomes dysfunctional, the brain can become susceptible to Alzheimer's disease and other disorders. Scientists, however, have not yet determined exactly how cerebrovascular problems and Alzheimer's are linked. One process in the blood that might offer a clue about this link is called the contact activation system. This process is involved in both inflammation and blood clotting, and changes to the contact system may lead to excessive, dementia-related inflammation problems and loss of blood flow in the brain.
In preliminary research, Sidney Strickland, Ph.D., and colleagues observed that the contact system is strongly activated in people with Alzheimer's disease and in mice genetically engineered to develop Alzheimer's-like pathology. They also found that by reducing levels of a key contact system protein, they could moderate inflammation and preserve memory and other cognitive functions in their mice. Taken together, these findings suggest that excessive activation of the contact system might play an important role in the development of dementia.
Dr. Strickland and colleagues now plan to clarify how the contact system affects brain health. The system uses two separate chemical pathways to trigger inflammation or blood clotting, however it is not clear if one of these pathways is more important than the other or if both are critical to promote dementia-related problems. To test their hypothesis, the researchers will use one drug treatment to block the inflammation pathway and another to block the blood clotting pathway in their Alzheimer's-like mice. They will then assess which procedure had the greatest effect on the animals' cognitive health and brain structure. Such work will involve state-of-the-art imaging procedures that can detect alterations in beta-amyloid levels and other brain changes.
The results of this project will refine our understanding of how blood-based abnormalities lead to Alzheimer's disease. They could also identify novel targets for future Alzheimer's drug treatments that change the course of the disease.