title: Toxicity in rat primary neurons through the cellular oxidative stress induced by the turn formation at positions 22 and 23 of Aβ42.
abstract: 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-Aβ42 in addition to potent neurotoxicity. Interestingly, the formation of the toxic conformer in both E22P-Aβ42 and Wt-Aβ42 probed by the 11A1 antibody preceded Aβ42-induced neurotoxicity. Trolox (a radical scavenger) and Congo red (an aggregation inhibitor) significantly prevented the neurotoxicity and intracellular ROS induced by E22P-Aβ42 and Wt-Aβ42, respectively. These results suggest that Aβ42-mediated toxicity is caused by the turn that favors toxic oligomers, which increase generation of ROS.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Izuo
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Mizuho
authors.initials: M
authors.lastname: Sato
authors.forename: Kazuma
authors.initials: K
authors.lastname: Murakami
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003224:Congo Red; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D011247:Pregnancy; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002839:Chromans; D016166:Free Radical Scavengers; D009498:Neurotoxins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D014810:Vitamin E; D003224:Congo Red; C022616:thiazolyl blue; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid