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2008 Grants - Seeds
Plasminogen Activator and Its Inhibitors in Alzheimer's Disease
Nicholas W. Seeds, Ph.D.
University of Colorado, Denver, Anschutz Medical Campus
2008 Investigator-Initiated Research Grant
The protein fragment beta-amyloid tends to accumulate into clumps called plaques in the Alzheimer brain. Studies have found that the enzyme plasmin can prevent these plaques by breaking down beta-amyloid and removing it from the brain. Plasmin is activated by other enzymes called plasminogen activators (tPAs). Scientists, however, do not know exactly how the tPA/plasmin system operates or how it breaks down beta-amyloid.
Nicholas W. Seeds, Ph.D., and colleagues believe that tPA/plasmin activity is reduced in the brains of people with Alzheimer's. This problem likely occurs when proteins that inhibit plasmin activity become elevated. Such proteins may include plasminogen activator inhibitor-1 (PAI-1) or neuroserpin.
Dr. Seeds' team plans to analyze the biological mechanisms underlying tPA/plasmin activity and its relationship to beta-amyloid production. First, the researchers will study autopsied brain tissue from people with and without Alzheimer's disease. They hypothesize that the Alzheimer brains will have reduced levels of plasmin activity, due to increased amounts of plasmin-inhibiting proteins. The team will then study mice engineered to lack the genes for either PAI-1 or neuroserpin. These mice should produce relatively low levels of beta-amyloid in their brains.
Results of Dr. Seeds' effort could offer new insights into the role of plasmin in Alzheimer progression. Future treatments for the disease could involve regulating the tPA/plasmin system.