The plasmin system is induced by and degrades amyloid-β aggregates

H. Michael Tucker, Muthoni Kihiko, Joseph N. Caldwell, Sarah Wright, Takeshi Kawarabayashi, Douglas Price, Donald Walker, Stephen Scheff, Joseph P. McGillis, Russell E. Rydel, Steven Estus

Research output: Contribution to journalArticlepeer-review

261 Scopus citations

Abstract

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

Original languageEnglish
Pages (from-to)3937-3946
Number of pages10
JournalJournal of Neuroscience
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2000

Keywords

  • Alzheimer's disease
  • Amyloid
  • Apoptosis
  • Gene induction
  • Plasmin
  • Proteolysis
  • Tissue plasminogen activator

ASJC Scopus subject areas

  • Neuroscience (all)

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