Toxicity in Rat PrimaryNeurons through the CellularOxidative Stress Induced by the Turn Formation at Positions 22 and23 of Aβ42

摘要

The 42-mer amyloid β-protein (Aβ42) aggregates to form soluble oligomers that cause memory loss and synaptotoxicity in Alzheimer’s disease (AD). Oxidative stress is closely related to the pathogenesis of AD. We previously identified the toxic conformer of Aβ42 with a turn at positions 22 and 23 (“toxic turn”) by solid-state NMR and demonstrated that a monoclonal antibody (11A1) against the toxic turn in Aβ42 mainly detected the oligomer in the brains of AD patients. Our recent study suggested that oxidative stress is a key factor of the oligomerization and cognitive impairment induced by Aβ overproduction in vivo. However, the involvement of the toxic conformer in Aβ42-induced oxidative damage remains unclear. To investigate this mechanism, we examined the levels of intracellular reactive oxygen species (ROS) and neurotoxicity in rat primary neurons using E22P-Aβ42, a mutant that induces a turn at positions 22 and 23, and E22V-Aβ42, a turn-preventing mutant. E22P-Aβ42,but not E22V-Aβ42, induced greater ROS production than Wt-Aβ42in addition to potent neurotoxicity. Interestingly, the formationof the toxic conformer in both E22P-Aβ42 and Wt-Aβ42 probedby the 11A1 antibody preceded Aβ42-induced neurotoxicity. Trolox(a radical scavenger) and Congo red (an aggregation inhibitor) significantlyprevented the neurotoxicity and intracellular ROS induced by E22P-Aβ42and Wt-Aβ42, respectively. These results suggest that Aβ42-mediatedtoxicity is caused by the turn that favors toxic oligomers, whichincrease generation of ROS.