Role of phenylalanine 20 in Alzheimer's amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity.
Senile plaques are a hallmark of Alzheimer's disease (AD), a neurodegenerative disease associated with cognitive decline and aging. Abeta(1-42) is the primary component of the senile plaque in AD brain and has been shown to induce protein oxidation in vitro and in vivo. Oxidative stress is extensive in AD brain. As a result, Abeta(1-42) has been proposed to play a central role in the pathogenesis of AD; however, the specific mechanism of neurotoxicity remains unknown. Recently, it has been proposed that long distance electron transfer from methionine 35 to the Cu(II) bound at the N terminus of Abeta(1-42) occurs via phenylalanine 20. Additionally, it was proposed that substitution of phenylalanine 20 of Abeta(1-42) by alanine [Abeta(1-42)F20A] would lessen the neurotoxicity induced by Abeta(1-42). In this study, we evaluate the predictions of this theoretical study by determining the oxidative stress and neurotoxic properties of Abeta(1-42)F20A relative to Abeta(1-42) in primary neuronal cell culture. Abeta(1-42)F20A induced protein oxidation and lipid peroxidation similar to Abeta(1-42) but to a lesser extent and in a manner inhibited by pretreatment of neurons with vitamin E. Additionally, Abeta(1-42)F20A affected mitochondrial function similar to Abeta(1-42), albeit to a lesser extent. Furthermore, the mutation does not appear to abolish the ability of the native peptide to reduce Cu(II). Abeta(1-42)F20A did not compromise neuronal morphology at 24 h incubation with neurons, but did so after 48 h incubation. Taken together, these results suggest that long distance electron transfer from methionine 35 through phenylalanine 20 may not play a pivotal role in Abeta(1-42)-mediated oxidative stress and neurotoxicity.
Boyd-Kimball
Debra
D
Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
Mohmmad Abdul
Hafiz
H
Reed
Tanea
T
Sultana
Rukhsana
R
Butterfield
D Allan
DA
D000544:Alzheimer Disease / Q000209:etiology; D000595:Amino Acid Sequence; D000682:Amyloid / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D000818:Animals; D018929:Cell Culture Techniques; D003300:Copper / Q000378:metabolism; D005260:Female; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D010649:Phenylalanine / Q000737:chemistry* / Q000235:genetics; D017354:Point Mutation; D011247:Pregnancy; D051381:Rats; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D010649:Phenylalanine; D003300:Copper