Barnham Kevin J, Ciccotosto Giuseppe D, Tickler Anna K, Ali Feda E, Smith Danielle G, Williamson Nicholas A, Lam Yuen-Han, Carrington Darryl, Tew Deborah, Kocak Gulcan, Volitakis Irene, Separovic Frances, Barrow Colin J, Wade John D, Masters Colin L, Cherny Robert A, Curtain Cyril C, Bush Ashley I, Cappai Roberto
Department of Pathology, The University of Melbourne and The Mental Health Research Institute of Victoria, Victoria 3010, Australia.
J Biol Chem. 2003 Oct 31;278(44):42959-65. doi: 10.1074/jbc.M305494200. Epub 2003 Aug 18.
The amyloid beta peptide is toxic to neurons, and it is believed that this toxicity plays a central role in the progression of Alzheimer's disease. The mechanism of this toxicity is contentious. Here we report that an Abeta peptide with the sulfur atom of Met-35 oxidized to a sulfoxide (Met(O)Abeta) is toxic to neuronal cells, and this toxicity is attenuated by the metal chelator clioquinol and completely rescued by catalase implicating the same toxicity mechanism as reduced Abeta. However, unlike the unoxidized peptide, Met(O)Abeta is unable to penetrate lipid membranes to form ion channel-like structures, and beta-sheet formation is inhibited, phenomena that are central to some theories for Abeta toxicity. Our results show that, like the unoxidized peptide, Met(O)Abeta will coordinate Cu2+ and reduce the oxidation state of the metal and still produce H2O2. We hypothesize that Met(O)Abeta production contributes to the elevation of soluble Abeta seen in the brain in Alzheimer's disease.
β-淀粉样肽对神经元有毒性，人们认为这种毒性在阿尔茨海默病的进展中起核心作用。这种毒性的机制存在争议。在此我们报告，甲硫氨酸-35的硫原子被氧化为亚砜的Aβ肽（Met(O)Aβ）对神经元细胞有毒性，这种毒性可被金属螯合剂氯碘羟喹减弱，并被过氧化氢酶完全消除，这意味着其毒性机制与还原型Aβ相同。然而，与未氧化的肽不同，Met(O)Aβ无法穿透脂质膜形成离子通道样结构，并且β-折叠的形成受到抑制，这些现象是一些Aβ毒性理论的核心。我们的结果表明，与未氧化的肽一样，Met(O)Aβ会与Cu2+配位并降低金属的氧化态，同时仍然会产生H2O2。我们推测，Met(O)Aβ的产生有助于阿尔茨海默病患者大脑中可溶性Aβ水平的升高。
