A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage.
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.
Zou
Kun
K
Department of Dementia Research, National Institute for Longevity Sciences, Obu, Aichi 474-8522, Japan.
Gong
Jian-Sheng
JS
Yanagisawa
Katsuhiko
K
Michikawa
Makoto
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000037:antagonists & inhibitors; D003470:Culture Media; D005290:Ferric Compounds / Q000378:metabolism; D007501:Iron / Q000037:antagonists & inhibitors; D015227:Lipid Peroxidation / Q000187:drug effects; D008670:Metals / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D015320:Tachykinins / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002614:Chelating Agents; D003470:Culture Media; D005290:Ferric Compounds; D008670:Metals; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D015320:Tachykinins; C078592:amyloid beta-protein (1-40); D013481:Superoxides; D003300:Copper; D007501:Iron; D001205:Ascorbic Acid