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.