The free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid β-peptide(25-35) toxicity but not from hydroxynonenal toxicity: Relevance to the free radical hypothesis of Alzheimer's disease

Amyloid β-peptide (Aβ) is a key factor in the neurotoxicity of Atzheimer's disease (AD). Recent research has shown that Aβ-mediated neurotoxicity involves free radicals and that Aβ peptides can initiate multiple membrane alterations, including protein oxidation and lipid peroxidation, eventually leading to neuronal cell death. Research also has emphasized the role of 4-hydroxynonenal (HNE), a downstream product of lipid peroxidation, in being able to mimic some of the effects of Aβ peptides. In the current investigation, electron paramagnetic resonance (EPR) studies of spin labeled cortical synaptosomal membrane proteins has been employed to study conformational changes in proteins, spectrophotometric methods have been used to measure protein carbonyl content, and the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for mitochondrial function has been used to study the effect of vitamin E on samples that were treated with Aβ or HNE. The free radical dependence of β- amyloid-associated toxicity was confirmed by the ability of the free radical scavenger vitamin E to prevent the toxic effects of Aβ. In contrast, HNE was still toxic in the presence of vitamin E. These results support our Aβ- associated free radical model for neurotoxicity in AD brain and are discussed with reference to potential therapeutic strategies for AD.