Review: Alzheimer's amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity.
Alzheimer's disease, the major dementing disorder of the elderly that affects over 4 million Americans, is related to amyloid beta-peptide, the principal component of senile plaques in Alzheimer's disease brain. Oxidative stress, manifested by protein oxidation and lipid peroxidation, among other alterations, is a characteristic of Alzheimer's disease brain. Our laboratory united these two observations in a model to account for neurodegeneration in Alzheimer's disease brain, the amyloid beta-peptide-associated oxidative stress model for neurotoxicity in Alzheimer's disease. Under this model, the aggregated peptide, perhaps in concert with bound redox metal ions, initiates free radical processes resulting in protein oxidation, lipid peroxidation, reactive oxygen species formation, cellular dysfunction leading to calcium ion accumulation, and subsequent neuronal death. Free radical antioxidants abrogate these findings. This review outlines the substantial evidence from multiidisciplinary approaches for amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity and protection against these oxidative processes and cell death by free radical scavengers. In addition, we review the strong evidence supporting the notion that the single methionine residue of amyloid beta-peptide is vital to the oxidative stress and neurotoxicological properties of this peptide. Further, we discuss studies that support the hypothesis that aggregated soluble amyloid beta-peptide and not fibrils per se are necessary for oxidative stress and neurotoxicity associated with amyloid beta-peptide.
Department of Chemistry, University of Kentucky, Lexington, Kentucky, 40506-0055, USA.
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Varadarajan
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Yatin
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Aksenova
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Butterfield
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D005609:Free Radicals / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D005609:Free Radicals