Toxicity in Rat Primary Neurons through the Cellular Oxidative Stress Induced by the Turn Formation at Positions 22 and 23 of A尾42
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- 作者：Naotaka Izuo ; Toshiaki Kume ; Mizuho Sato ; Kazuma Murakami ; Kazuhiro Irie ; Yasuhiko Izumi ; Akinori Akaike
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：September 19, 2012
- 年：2012
- 卷：3
- 期：9
- 页码：674-681
- 全文大小：464K
- 年卷期：v.3,no.9(September 19, 2012)
- ISSN：1948-7193
文摘
The 42-mer amyloid 尾-protein (A尾42) aggregates to form soluble oligomers that cause memory loss and synaptotoxicity in Alzheimer鈥檚 disease (AD). Oxidative stress is closely related to the pathogenesis of AD. We previously identified the toxic conformer of A尾42 with a turn at positions 22 and 23 (鈥渢oxic turn鈥? by solid-state NMR and demonstrated that a monoclonal antibody (11A1) against the toxic turn in A尾42 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 A尾 overproduction in vivo. However, the involvement of the toxic conformer in A尾42-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-A尾42, a mutant that induces a turn at positions 22 and 23, and E22V-A尾42, a turn-preventing mutant. E22P-A尾42, but not E22V-A尾42, induced greater ROS production than Wt-A尾42 in addition to potent neurotoxicity. Interestingly, the formation of the toxic conformer in both E22P-A尾42 and Wt-A尾42 probed by the 11A1 antibody preceded A尾42-induced neurotoxicity. Trolox (a radical scavenger) and Congo red (an aggregation inhibitor) significantly prevented the neurotoxicity and intracellular ROS induced by E22P-A尾42 and Wt-A尾42, respectively. These results suggest that A尾42-mediated toxicity is caused by the turn that favors toxic oligomers, which increase generation of ROS.