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标题：Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity
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作者：Mahmoud B. Maina ; Gunasekhar Burra ; Youssra K. Al-Hilaly 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：10
页码：1-21
DOI：10.1016/j.isci.2020.101537
语种：English
出版社：Elsevier
摘要：SummaryDityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-β (Aβ) forms DiYin vitroand DiY-cross-linked Aβ is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of Aβ42 results in an increase in DiY cross-links. Using DiY as a marker of oxidation, we compare the self-assembly propensity and DiY cross-link formation for a non-assembly competent variant of Aβ42 (vAβ) with wild-type Aβ42. Oxidation results in the formation of trapped wild-type Aβ assemblies with increased DiY cross-links that are unable to elongate further. Assembly-incompetent vAβ and trapped Aβ assemblies are non-toxic to neuroblastoma cells at all stages of self-assembly, in contrast to oligomeric, non-cross-linked Aβ. These findings point to a mechanism of toxicity that necessitates dynamic self-assembly whereby trapped Aβ assemblies and assembly-incompetent variant Aβ are unable to result in cell death.Graphical AbstractDisplay OmittedHighlights•Metal- (Cu2+H202) or UV- catalyzedoxidation results in dityrosine (DiY) formation•Oxidation results in DiY cross-link formation in Aβ and halts further assembly•Non-assembling Aβ (trapped Aβ or variant Αβ monomer) is not cytotoxicBiochemical Mechanism; Molecular Neuroscience; Neurotoxicology