The antioxidant vitamin E modulates amyloid beta-peptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of Alzheimer's disease.
Amyloid beta-peptide (Abeta), the main constituent of senile plaques in Alzheimer's disease (AD) brain, is hypothesized to be a key factor in the neurodegeneration seen in AD. Recently it has been shown by us and others that the neurotoxicity of Abeta occurs in conjunction with free radical oxidative stress associated with the peptide. Abeta(1-40) and several other fragments of the Abeta sequence are associated with free radicals in solution that are detectable using electron paramagnetic resonance spectroscopy. These free radicals were shown to attack brain cell membranes, initiate lipid peroxidation, increase Ca2+ influx and damage membrane and cytosolic proteins. In AD brain obtained under rapid autopsy protocol, the activity of the oxidatively-sensitive enzyme creatine kinase was shown to be significantly reduced. We reasoned that Abeta-associated free radical-induced modification of creatine kinase activity and other markers of cellular damage might be modulated by free radical scavengers. Accordingly, this study demonstrates that vitamin E can modulate Abeta(25-35)-induced oxidative damage to creatine kinase and cellular proteins in cultured embryonic hippocampal neurons. These results, consistent with the hypothesis of free radical-mediated Abeta toxicity in AD, are discussed with deference to potential free radical scavengers as therapeutic agents for slowing the progression of AD.
Yatin
S M
SM
Department of Chemistry and Center of Membrane Sciences, University of Kentucky Lexington, 40506-0055, USA.
Aksenov
M
M
Butterfield
D A
DA
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000037:antagonists & inhibitors*; D004578:Electron Spin Resonance Spectroscopy; D004622:Embryo, Mammalian; D005609:Free Radicals; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D005609:Free Radicals; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D014810:Vitamin E; D003402:Creatine Kinase