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The Plasmin System Is Induced by and Degrades Amyloid- Aggregates

H. Michael Tucker¹, Muthoni Kihiko¹, Joseph N. Caldwell¹, Sarah Wright⁵, Takeshi Kawarabayashi⁴, Douglas Price², Donald Walker⁵, Stephen Scheff², Joseph P. McGillis³, Russell E. Rydel⁵, and Steven Estus¹

¹ Department of Physiology, ² Department of Anatomy and Neurobiology, Sanders-Brown Center on Aging, and ³ Department of Microbiology and Immunology, University of Kentucky, Lexington, Kentucky 40536, ⁴ Mayo Clinic, Jacksonville, Florida 32224, and ⁵ Elan Pharmaceuticals, Inc., South San Francisco, California 94080

Amyloid- (A) appears critical to Alzheimer's disease. To clarify possible mechanisms of A action, we have quantified A-induced gene expression in vitro by using A-treated primary cortical neuronal cultures and in vivo by using mice transgenic for the A precursor (AP). Here, we report that aggregated, but not nonaggregated, A increases the level of the mRNAs encoding tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Moreover, tPA and uPA were also upregulated in aged AP overexpressing mice. Because others have reported that A aggregates can substitute for fibrin aggregates in activating tPA post-translationally, the result of tPA induction by A would be cleavage of plasminogen to the active protease plasmin. To gain insights into the possible actions of plasmin, we evaluated the hypotheses that tPA and plasmin may mediate A in vitro toxicity or, alternatively, that plasmin activation may lead to A degradation. In evaluating these conflicting hypotheses, we found that purified plasmin degrades A with physiologically relevant efficiency, i.e., ~1/10th the rate of plasmin on fibrin. Mass spectral analyses show that plasmin cleaves A at multiple sites. Electron microscopy confirms indirect assays suggesting that plasmin degrades A fibrils. Moreover, exogenously added plasmin blocks A neurotoxicity. In summation, we interpret these results as consistent with the possibility that the plasmin pathway is induced by aggregated A, which can lead to A degradation and inhibition of A actions.

Key words: amyloid; plasmin; tissue plasminogen activator; apoptosis; gene induction; Alzheimer's disease; proteolysis

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20113937-10$05.00/0

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