A Novel Function of Monomeric Amyloid β-Protein Serving as an Antioxidant Molecule against Metal-Induced Oxidative Damage

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Abstract
Aggregated and oligomeric amyloid β-protein (Aβ) is known to exhibit neurotoxicity. However, the action of Aβ monomers on neurons is not fully understood. We have studied aggregation state-dependent actions of Aβ and found an oligomer-specific effect of Aβ on lipid metabolism in neurons (Michikawa et al., 2001). Here, we show a novel function of monomeric Aβ1–40, 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 Aβ1–40, which is demonstrated by SDS-PAGE after treatment with glutaraldehyde, protects neurons cultured in a medium containing 1.5 μm 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 Aβ1–40 inhibits neuronal death caused by Cu(II), Fe(II), and Fe(III) but does not protect neurons against H2O2-induced damage. Monomeric Aβ1–40 inhibits the reduction of Fe(III) induced by vitamin C and the generation of superoxides and prevents lipid peroxidation induced by Fe(II). Aβ1–42 remaining as a monomer also exhibits antioxidant and neuroprotective effects. In contrast, oligomeric and aggregated Aβ1–40 and Aβ1–42 lose their neuroprotective activity. These results indicate that monomeric Aβ protects neurons by quenching metal-inducible oxygen radical generation and thereby inhibiting neurotoxicity. Because aggregated Aβ is known to be an oxygen radical generator, our results provide a novel concept that the aggregation-dependent biological effects of Aβ are dualistic, being either an oxygen radical generator or its inhibitor.