A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage

J Neurosci. 2002 Jun 15;22(12):4833-41. doi: 10.1523/JNEUROSCI.22-12-04833.2002.


Aggregated and oligomeric amyloid beta-protein (Abeta) is known to exhibit neurotoxicity. However, the action of Abeta monomers on neurons is not fully understood. We have studied aggregation state-dependent actions of Abeta and found an oligomer-specific effect of Abeta on lipid metabolism in neurons (Michikawa et al., 2001). Here, we show a novel function of monomeric Abeta1-40, which is the major species found in physiological fluid, as a natural antioxidant molecule that prevents neuronal death caused by transition metal-induced oxidative damage. Monomeric Abeta1-40, which is demonstrated by SDS-PAGE after treatment with glutaraldehyde, protects neurons cultured in a medium containing 1.5 microm Fe(II) without antioxidant molecules. Metal ion chelators such as EDTA, CDTA (trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid), and DTPA (diethylenetriamine-N,N,N',N",N"-penta-acetic acid, an iron-binding protein, transferrin, and antioxidant scavengers such as catalase, glutathione, and vitamin E also inhibit neuronal death under the same conditions. Monomeric Abeta1-40 inhibits neuronal death caused by Cu(II), Fe(II), and Fe(III) but does not protect neurons against H2O2-induced damage. Monomeric Abeta1-40 inhibits the reduction of Fe(III) induced by vitamin C and the generation of superoxides and prevents lipid peroxidation induced by Fe(II). Abeta1-42 remaining as a monomer also exhibits antioxidant and neuroprotective effects. In contrast, oligomeric and aggregated Abeta1-40 and Abeta1-42 lose their neuroprotective activity. These results indicate that monomeric Abeta protects neurons by quenching metal-inducible oxygen radical generation and thereby inhibiting neurotoxicity. Because aggregated Abeta is known to be an oxygen radical generator, our results provide a novel concept that the aggregation-dependent biological effects of Abeta are dualistic, being either an oxygen radical generator or its inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Antioxidants / pharmacology*
  • Ascorbic Acid / antagonists & inhibitors
  • Cell Death / drug effects
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Copper / antagonists & inhibitors
  • Culture Media
  • Ferric Compounds / metabolism
  • Iron / antagonists & inhibitors
  • Lipid Peroxidation / drug effects
  • Metals / antagonists & inhibitors*
  • Neurons / cytology*
  • Neurons / drug effects
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects*
  • Peptide Fragments / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Superoxides / metabolism
  • Tachykinins / pharmacology


  • Amyloid beta-Peptides
  • Antioxidants
  • Chelating Agents
  • Culture Media
  • Ferric Compounds
  • Metals
  • Neuroprotective Agents
  • Peptide Fragments
  • Tachykinins
  • amyloid beta-protein (1-40)
  • Superoxides
  • Copper
  • Iron
  • Ascorbic Acid