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Molecular System Involved In Blood Clotting May Play A Role In Alzheimer's Disease

Date:
June 7, 2000
Source:
University Of Kentucky Medical Center
Summary:
The molecular system that regulates blood clotting, called the plasmin system, also may be involved in the development of Alzheimer's disease, according to a study led by researchers at the University of Kentucky Chandler Medical Center and published in the June 1 issue of The Journal of Neuroscience.
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The molecular system that regulates blood clotting, called the plasmin system, also may be involved in the development of Alzheimer's disease, according to a study led by researchers at the University of Kentucky Chandler Medical Center and published in the June 1 issue of The Journal of Neuroscience.

Because of its role in Alzheimer's disease, the molecules involved in the plasmin system may lead to treatments for Alzheimer's disease. The study was led by Steven Estus, Ph.D., assistant professor, and H. Michael Tucker, Ph.D., researcher, both in the Department of Physiology at the UK College of Medicine and the UK Sanders-Brown Center on Aging.

About 60,000 Kentuckians have Alzheimer's disease, and, nationally, 4 million people are estimated to have the disease. A protein called amyloid-beta is thought to be critical in the development of Alzheimer's disease, although the exact role of amyloid-beta is unknown. Aggregated amyloid-beta proteins, also called amyloid fibrils, are found in the brains of Alzheimer's patients.

Blood clots routinely form in blood vessels. It is crucial that these clots be destroyed before they cause heart attacks or strokes. This destruction is accomplished by activating the plasmin system. The plasmin system regulates the process of blood clotting and also plays a role in cell migration. The principal molecules involved in regulating blood clots are plasminogen/plasmin, tissue plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor (PAI-1), and alpha-2-antiplasmin (a2-AP). The U.S. Food and Drug Administration has approved synthetic tPA for use in treating heart attacks or strokes within a few hours of the onset of symptoms. The drug dissolves the blood clot that is causing the heart attack or stroke.

The first step in destroying blood clots is the production of the proteins tPA and uPA in tissues near the blood clot. These two proteins cut the molecule plasminogen to form plasmin. Plasmin then destroys the target protein. In the case of blood clots, the target is a protein called fibrin. PAI-1 and a2-AP work to control the process by inhibiting the activity of tPA and uPA.

"The tPA protein also binds to clumps of amyloid-beta protein. So what we needed to explore was whether plasmin destroys amyloid-beta as it does fibrin and whether plasmin exhibits any neurotoxic effects," Estus said.

The results showed that aggregated amyloid-beta stimulates the production of both tPA and uPA, that plasmin destroys non-aggregated and aggregated amyloid-beta proteins as well as it destroys fibrin, and that plasmin appears to have no direct toxic effects in the brain.

Also, previous research has shown that the amount of the protein PAI-1, which inhibits the activity of tPA, is increased in Alzheimer's disease and inflammation, a common symptom of Alzheimer's.

"With these results and previous research, we can suggest a model of the development of Alzheimer's disease. Specifically, inflammation increases the amount of tPA inhibitors, which prevents the destruction of amyloid-beta proteins by obstructing the action of tPA. The increased levels of amyloid-beta cause further inflammation that feeds the cycle again," Tucker said.

"The particularly exciting thing about these results is that they suggest that it may be possible to treat Alzheimer's disease by destroying amyloid-beta protein deposits with tPA that is modified to target brain tissue," Estus said.

Further research will explore the accuracy of this model and whether tPA can be modified effectively to target brain tissue.

The study was funded by American Health Assistance Foundation, a private foundation that supports Alzheimer's disease research


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The above post is reprinted from materials provided by University Of Kentucky Medical Center. Note: Materials may be edited for content and length.


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University Of Kentucky Medical Center. "Molecular System Involved In Blood Clotting May Play A Role In Alzheimer's Disease." ScienceDaily. ScienceDaily, 7 June 2000. <www.sciencedaily.com/releases/2000/06/000602074152.htm>.
University Of Kentucky Medical Center. (2000, June 7). Molecular System Involved In Blood Clotting May Play A Role In Alzheimer's Disease. ScienceDaily. Retrieved August 30, 2015 from www.sciencedaily.com/releases/2000/06/000602074152.htm
University Of Kentucky Medical Center. "Molecular System Involved In Blood Clotting May Play A Role In Alzheimer's Disease." ScienceDaily. www.sciencedaily.com/releases/2000/06/000602074152.htm (accessed August 30, 2015).

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