Plasmin Cleavage of the Amyloid Beta-Protein: Alteration of Secondary Structure and Stimulation of Tissue Plasminogen Activator Activity

Biochemistry. 1999 Aug 31;38(35):11570-6. doi: 10.1021/bi990610f.

Abstract

Cerebrovascular amyloid beta-protein (A beta) deposition, a key pathological feature of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis Dutch-type, can lead to intracerebral hemorrhage; however, the mechanism for this remains unclear. Assembled A beta is a potent stimulator of tissue-type plasminogen activator (tPA) in vitro. Herein, we investigated the stimulation of tPA by freshly solubilized A beta 1-40. The rate of tPA stimulation by A beta 1-40 increased dramatically over time, suggesting that A beta may be altered during the course of the reaction. SDS-PAGE analysis showed that A beta 1-40 was cleaved during the course of the reaction. Subsequent studies showed that it was plasmin, the product of tPA activation of plasminogen, that specifically cleaved A beta 1-40 in the amino terminal region between Arg5 and His6. Plasmin effectively cleaved a chromogenic substrate corresponding to this cleavage site in A beta. Circular dichroism spectral analysis showed that A beta 6-40 adopted a strong beta-sheet secondary structure. This truncated A beta 6-40 peptide was a potent stimulator of tPA in vitro. Our results indicate that beta-sheet secondary structure of A beta, which can be promoted by plasmin cleavage, stimulates tPA activity. These findings suggest that pathologic interactions between A beta, tPA, and plasmin in the cerebral vessel wall could result in excessive proteolysis contributing to intracerebral hemorrhages.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Arginine / metabolism
  • Circular Dichroism
  • Enzyme Activation
  • Fibrinolysin / metabolism*
  • Histidine / metabolism
  • Humans
  • Hydrolysis
  • Kinetics
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism*
  • Protein Processing, Post-Translational
  • Protein Structure, Secondary
  • Tissue Plasminogen Activator / metabolism*

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (6-25)
  • Histidine
  • Arginine
  • Tissue Plasminogen Activator
  • Fibrinolysin