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

Abstract

Amyloid β-peptide (Aβ) of 39-42 amino acid residues is a major constituent of Alzheimer's disease neurite plaques. Aβ 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 Aβ aggregates possess the multiple valencies of an FAED motif (20th to 23rd amino acid residues), which resembles the putative transforming growth factor-β (TGF-β) active site motif, we hypothesize that Aβ monomers and Aβ aggregates may function as TGF-β antagonists and partial agonists, analogous to previously described monovalent and multivalent TGF-β 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 Aβ monomer, Aβ-(1-40) and its fragment, containing the motif inhibit radiolabeled TGF-β binding to cell- surface TGF-β receptors in mink lung epithelial cells (Mv1Lu cells). Aβ- (1-40)-bovine serum albumin conjugate (Aβ-(1-40)-BSA), a multivalent synthetic analogue of Aβ aggregates, exhibited cytotoxicity toward bovine cerebral endothelial cells and rat postmitotic differentiated hippocampal neuronal cells (H19-7 cells) and inhibitory activities of radiolabeled TGF- β binding to TGF-β receptors and TGF-β-induced plasminogen activator inhibitor-1 expression, that were ~100-670 times more potent than those of Aβ-(1-40) monomers. At less than micromolar concentrations, Aβ-(1-40) -BSA but not Aβ-(1-40) monomers inhibited proliferation of Mv1Lu cells. Since TGF-β is an organizer of responses to neurodegeneration and is also found in neurite plaques, the TGF-β antagonist and partial agonist activities of Aβ monomers and aggregates may play an important role in the pathogenesis of the disease.