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The Journal of Neuroscience, October 1, 2003, 23(26):8867-8871
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BRIEF COMMUNICATION
The Tissue Plasminogen Activator-Plasminogen Proteolytic Cascade Accelerates Amyloid- (A) Degradation and Inhibits A-Induced Neurodegeneration
Jerry P. Melchor,
Robert Pawlak, and
Sidney Strickland
Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York 10021
Accumulation of the amyloid- (A) peptide depends on both its generation and clearance. To better define clearance pathways, we have evaluated the role of the tissue plasminogen activator (tPA)-plasmin system in A degradation in vivo. In two different mouse models of Alzheimer's disease, chronically elevated A peptide in the brain correlates with the upregulation of plasminogen activator inhibitor-1 (PAI-1) and inhibition of the tPA-plasmin system. In addition, A injected into the hippocampus of mice lacking either tPA or plasminogen persists, inducing PAI-1 expression and causing activation of microglial cells and neuronal damage. Conversely, A injected into wild-type mice is rapidly cleared and does not cause neuronal degeneration. Thus, the tPA-plasmin proteolytic cascade aids in the clearance of A, and reduced activity of this system may contribute to the progression of Alzheimer's disease.
Key words: Alzheimer's disease; neurodegeneration; protease; amyloid- degradation; plasmin; PAI-1
Received July 10, 2003;
revised August 7, 2003;
accepted August 8, 2003.
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