Role of Phenylalanine 20 in Alzheimer's Amyloid β-peptide (1-42)-induced Oxidative Stress and Neurotoxicity
Author ORCID Identifier
Tanea Reed
https://orcid.org/0000-0003-2642-3100
Department
Chemistry
Document Type
Article
Publication Date
1-1-2004
Abstract
Senile plaques are a hallmark of Alzheimer's disesae (AD), a neurodegenerative disease associated with cognitive decline and aging. Aβ(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, Aβ(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 Aβ(1-42) occurs via phenylalanine 20. Additionally, it was proposed that substitution of phenylalanine 20 of Aβ(1-42) by alanine [Aβ(1-42)F20A] would lessen the neurotoxicity induced by Aβ(1-42). In this study, we evaluate the predictions of this theoretical study by determining the oxidative stress and neurotoxic properties of Aβ(1-42)F20A relative to Aβ(1-42) in primary neuronal cell culture. Aβ(1-42)F20A induced protein oxidation and lipid peroxidation similar to Aβ(1-42) but to a lesser extent and in a manner inhibited by pretreatment of neurons with vitamin E. Additionally, Aβ(1-42)F20A affected mitochrondrial function similar to Aβ(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). Aβ(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 Aβ(1-42)-mediated oxidative stress and neurotoxicity.
Recommended Citation
Boyd-Kimball, Debra; Abdul, Hafiz Mohmmad; Reed, Tanea T.; Sultana, Rukhsana; and Butterfield, D. Allan, "Role of Phenylalanine 20 in Alzheimer's Amyloid β-peptide (1-42)-induced Oxidative Stress and Neurotoxicity" (2004). EKU Faculty and Staff Scholarship. 648.
https://encompass.eku.edu/fs_research/648
Journal Title
Chemical Research in Toxicology
