Hydrogen Peroxide Modifies Aβ-Membrane Interactions with Implications for Aβ 40 Aggregation.

Alzheimer's disease (AD) is pathologically characterized by the formation of extracellular senile plaques, predominately comprised of aggregated beta-amyloid (A beta), deposited in the brain. A beta aggregation can result in a myriad of distinct aggregate species, from soluble oligomers to insoluble fibrils. A beta strongly interacts with membranes, which can be linked to a variety of potential toxic mechanisms associated with AD. Oxidative damage accompanies the formation of A beta aggregates, with a 10-50% proportion of A beta aggregates being oxidized in vivo. Hydrogen peroxide (H2O2) is a reactive oxygen species implicated in a number of neurodegenerative diseases. Recent evidence has demonstrated that the H2O2 concentration fluctuates rapidly in the brain, resulting in large concentration spikes, especially in the synaptic cleft. Here, the impact of environmental H2O2 on A beta aggregation in the presence and absence of lipid membranes is investigated. A beta(40) was exposed to H2O2 resulting in the selective oxidation of methionine 35 (Met35) to produce A beta(40)Met35[O]. While oxidation mildly reduced the rate of A beta aggregation and produced a distinct fibril morphology at high H2O2 concentrations, H2O2 had a much more pronounced impact on A beta aggregation in the presence of total brain lipid extract vesicles. The impact of H2O2 on A beta aggregation in the presence of lipids was associated with a reduced affinity of A beta for the vesicle surface. However, this reduced vesicle affinity was predominately associated with lipid peroxidation rather than A beta oxidation.