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The Journal of Neuroscience, June 15, 2002, 22(12):4833-4841
A Novel Function of Monomeric Amyloid  -Protein Serving as an
Antioxidant Molecule against Metal-Induced Oxidative Damage
Kun
Zou,
Jian-Sheng
Gong,
Katsuhiko
Yanagisawa, and
Makoto
Michikawa
Department of Dementia Research, National Institute for Longevity
Sciences, Obu, Aichi 474-8522, Japan
Aggregated and oligomeric amyloid  -protein (A) is known
to exhibit neurotoxicity. However, the action of A monomers on neurons is not fully understood. We have studied aggregation
state-dependent actions of A and found an oligomer-specific effect
of A on lipid metabolism in neurons (Michikawa et al., 2001). Here,
we show a novel function of monomeric A1-40, 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 A1-40, 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 A1-40 inhibits
neuronal death caused by Cu(II), Fe(II), and Fe(III) but does not
protect neurons against H2O2-induced damage.
Monomeric A1-40 inhibits the reduction of Fe(III) induced by
vitamin C and the generation of superoxides and prevents lipid
peroxidation induced by Fe(II). A1-42 remaining as a monomer also
exhibits antioxidant and neuroprotective effects. In contrast,
oligomeric and aggregated A1-40 and A1-42 lose their
neuroprotective activity. These results indicate that monomeric A
protects neurons by quenching metal-inducible oxygen radical generation
and thereby inhibiting neurotoxicity. Because aggregated A is known
to be an oxygen radical generator, our results provide a novel concept
that the aggregation-dependent biological effects of A are
dualistic, being either an oxygen radical generator or its inhibitor.
Key words:
Alzheimer's disease; amyloid -protein; transition
metals; oxygen radicals; antioxidant; neuronal death
Copyright © 2002 Society for Neuroscience 0270-6474/02/22124833-09$05.00/0
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