Amyloid beta-peptide possesses a transforming growth factor-beta activity

J Biol Chem. 1998 Oct 16;273(42):27640-4. doi: 10.1074/jbc.273.42.27640.

Abstract

Amyloid beta-peptide (Abeta) of 39-42 amino acid residues is a major constituent of Alzheimer's disease neurite plaques. Abeta aggregates (fibrils) are believed to be responsible for neuronal damage and dysfunction, as well as microglia and astrocyte activation in disease lesions by multiple mechanisms. Since Abeta aggregates possess the multiple valencies of an FAED motif (20th to 23rd amino acid residues), which resembles the putative transforming growth factor-beta (TGF-beta) active site motif, we hypothesize that Abeta monomers and Abeta aggregates may function as TGF-beta antagonists and partial agonists, analogous to previously described monovalent and multivalent TGF-beta peptide antagonists and agonists (Huang, S. S., Liu, Q., Johnson, F. E., Konish, Y., and Huang, J. S. (1997) J. Biol. Chem. 272, 27155-27159). Here, we report that the Abeta monomer, Abeta-(1-40) and its fragment, containing the motif inhibit radiolabeled TGF-beta binding to cell-surface TGF-beta receptors in mink lung epithelial cells (Mv1Lu cells). Abeta-(1-40)-bovine serum albumin conjugate (Abeta-(1-40)-BSA), a multivalent synthetic analogue of Abeta aggregates, exhibited cytotoxicity toward bovine cerebral endothelial cells and rat post-mitotic differentiated hippocampal neuronal cells (H19-7 cells) and inhibitory activities of radiolabeled TGF-beta binding to TGF-beta receptors and TGF-beta-induced plasminogen activator inhibitor-1 expression, that were approximately 100-670 times more potent than those of Abeta-(1-40) monomers. At less than micromolar concentrations, Abeta-(1-40)-BSA but not Abeta-(1-40) monomers inhibited proliferation of Mv1Lu cells. Since TGF-beta is an organizer of responses to neurodegeneration and is also found in neurite plaques, the TGF-beta antagonist and partial agonist activities of Abeta monomers and aggregates may play an important role in the pathogenesis of the disease.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Cattle
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Immunoconjugates
  • Lung / cytology
  • Mink
  • Molecular Sequence Data
  • Neurons / cytology
  • Neurons / drug effects
  • Plasminogen Activator Inhibitor 1 / biosynthesis
  • Rats
  • Receptors, Transforming Growth Factor beta / deficiency
  • Serum Albumin, Bovine
  • Signal Transduction
  • Transforming Growth Factor beta / agonists
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Immunoconjugates
  • Plasminogen Activator Inhibitor 1
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Serum Albumin, Bovine