tPA and Plasmin Modulate Amyloid Beta

Steven Estus, PhD
University of Kentucky Research Foundation (Lexington, KY)
Year Awarded:
1999
Grant Duration:
April 1, 1999 to March 31, 2000
Disease:
Alzheimer's Disease
Award Amount:
$196,151
Grant Reference ID:
A1999048
Award Type:
Standard
Award Region:
US Southeastern

tPA and Plasmin Modulate Amyloid Beta

Details


Dr. Estus is focusing on the clearance of beta-amyloid (Ab) by a protease, or an enzyme that digests proteins, called plasmin. Plasmin is normally converted from an inactive form, called plasminogen, to the active form by a protease called tissue plasminogen activator (tPA). Dr. Estus has found that Ab can increase the production of tPA in neuronal cells in culture and that Ab can activate tPA to digest plasminogen into the active plasmin. Plasmin can in turn digest Ab into small fragments. On the basis of these observations, Dr. Estus has hypothesized that Ab causes the increased plasmin activity, which then degrades Ab by proteolysis, and that plasmin serves a protective function by clearing Ab from the brain. In addition, an inhibitor of plasmin production, called plasminogen activator inhibitor (PAI-1), is increased during the inflammation that occurs in Alzheimer's disease. Dr. Estus proposes a "feed forward" model in which inflammation during Alzheimer's disease causes PAI-1 production, which inhibits plasmin. Plasmin inhibition results in more Ab production, damage, and inflammation, perpetuating the cycle. To evaluate this model, Dr. Estus will determine if the results observed in vitro occur in a living system by using genetically engineered mice that either over-produce tPA or are deficient in tPA. This study was partially funded through the Irwin Lee Challenge Grant.

Publications

H. M. Tucker, M. Kihiko, J. N. Caldwell, S. Wright, D. Price, S. Scheff, J. P. McGillis, R. E. Rydel, and S. Estus. The plasmin system regulates amyloid- beta levels and actions in vitro. J. Neurosci. 20: 3937-3946 (2000).  

H. M. Tucker, M. Kihiko-Ehmann, S. Wright, R. E. Rydel, and S. Estus. Tissue plasminogen activator requires plasminogen to modulate amyloid-beta neurotoxicity and deposition. J. Neurochem. 75: 2172-2177 (2000).  

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