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

Abstract

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.

Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

“…32,33 Recent studies suggested that monomeric (soluble) Ab acts as a natural antioxidant that prevents neuronal cell death caused by oxidative stress, whereas fibrillar Ab is an ROS generator and neurotoxic. 34 Gly33 and Met35 of Ab 1-42 peptide have been reported to be essential for ROS production and neurotoxicity. 35 However, the precise molecular mechanism by which Ab leads to neuronal cell death has not been elucidated.…”

“…Ab [25][26][27][28][29][30][31][32][33][34][35] and Ab 1-42 were purchased from Bachem and American Peptide Company, respectively. Ab [25][26][27][28][29][30][31][32][33][34][35] was dissolved in water at 1 mM and Ab was dissolved in water containing 0.1% NH 3 at 1 mM.…”

“…Ab [25][26][27][28][29][30][31][32][33][34][35] was dissolved in water at 1 mM and Ab was dissolved in water containing 0.1% NH 3 at 1 mM. Dissolved Ab peptides were mixed with the same volume of PBS and incubated at 371C for 3-5 days before use.…”

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

“…Physiologic functions of A β are not well‐established, but significant lines of evidence suggest that A β may have potential protective properties under certain conditions. A β 42 has been shown to have antioxidant effects and decrease the oxidation of lipoproteins in the cerebrospinal fluid (CSF) and blood plasma 11, 12. A study utilizing different experimental autoimmune encephalomyelitis models, demonstrated that the peripherally augmented levels of A β 40 and A β 42 effectively suppressed inflammation in different organs, thus attenuating autoimmune inflammation targeting the central nervous system (CNS) 13.…”

Promotion of Oxidative Lipid Membrane Damage by Amyloid β Proteins

“…The density of plaques containing Aβ protein correlates inversely with markers of oxidative damage (42), and in Downs syndrome, cortical deposition of Aβ proteins correlates with reduced oxidative damage (43). Moreover, Aβ proteins prevent lipoprotein oxidation (37) and metal-induced neuronal death in culture (44).…”