Hypochlorite-induced oxidation promotes aggregation and reduces toxicity of amyloid beta 1-42.
Hypochlorite-induced oxidation promotes aggregation and reduces toxicity of amyloid beta 1-42.
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DOI：
10.1016/j.redox.2023.102736
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发表时间：
2023-07
期刊：
影响因子：
11.4
通讯作者：
Wyatt, Amy R.
中科院分区：
文献类型：
--
作者：
Manucat-Tan, Noralyn B.;Chowdhury, Ashfaq;Cataldi, Rodrigo;Abdullah, Rafaa Zeineddine;Kumita, Janet R.;Wyatt, Amy R.
关键词：
次氯酸盐（OCl⁻）生成的加剧与神经退行性过程有关，但越来越多的证据表明，较低水平的次氯酸盐活性对蛋白质稳态很重要。在这项研究中，我们描述了次氯酸盐对淀粉样β肽1 - 42（Aβ1 - 42）的聚集和毒性的影响，Aβ1 - 42是阿尔茨海默病患者大脑中形成的淀粉样斑块的主要成分。我们的结果表明，次氯酸盐处理促进了≥100 kDa的Aβ1 - 42聚集体的形成，与未处理的肽相比，其表面暴露的疏水性降低。通过质谱分析确定，这种效应是Aβ1 - 42在单个位点被氧化的结果。尽管次氯酸盐处理促进了Aβ1 - 42的聚集，但通过滤膜捕获分析、硫黄素T分析和透射电子显微镜评估，肽的溶解性增强，淀粉样纤维形成受到抑制。使用SH - SY5Y神经母细胞瘤细胞进行的体外分析结果表明，用亚化学计量的次氯酸盐对Aβ1 - 42进行预处理可大大降低其毒性。流式细胞术分析和内化分析的结果表明，次氯酸盐诱导的Aβ1 - 42修饰通过至少两种不同的机制降低其毒性，即减少Aβ1 - 42与细胞表面的总结合，并促进Aβ1 - 42在细胞表面向溶酶体的清除。我们的数据与一种模型相符，即大脑中严格调控的次氯酸盐产生对Aβ诱导的毒性具有保护作用。
Exacerbated hypochlorite (OCl−) production is linked to neurodegenerative processes, but there is growing evidence that lower levels of hypochlorite activity are important to protein homeostasis. In this study we characterise the effects of hypochlorite on the aggregation and toxicity of amyloid beta peptide 1–42 (Aβ1-42), a major component of amyloid plaques that form in the brain in Alzheimer's disease. Our results demonstrate that treatment with hypochlorite promotes the formation of Aβ1-42 assemblies ≥100 kDa that have reduced surface exposed hydrophobicity compared to the untreated peptide. This effect is the result of the oxidation of Aβ1-42 at a single site as determined by mass spectrometry analysis. Although treatment with hypochlorite promotes the aggregation of Aβ1-42, the solubility of the peptide is enhanced and amyloid fibril formation is inhibited as assessed by filter trap assay, thioflavin T assay and transmission electron microscopy. The results of in vitro assays using SH-SY5Y neuroblastoma cells show that pre-treatment of Aβ1-42 with a sub-stoichiometric amount of hypochlorite substantially reduces its toxicity. The results of flow cytometry analysis and internalisation assays indicate that hypochlorite-induced modification of Aβ1-42 reduces its toxicity via at least two-distinct mechanism, reducing the total binding of Aβ1-42 to the surface of cells and facilitating the cell surface clearance of Aβ1-42 to lysosomes. Our data is consistent with a model in which tightly regulated production of hypochlorite in the brain is protective against Aβ-induced toxicity.
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影响因子：
4.6
作者：
Gu M;Bode DC;Viles JH
通讯作者：
Viles JH
影响因子：
7.1
作者：
Al-Hilaly YK;Williams TL;Stewart-Parker M;Ford L;Skaria E;Cole M;Bucher WG;Morris KL;Sada AA;Thorpe JR;Serpell LC
通讯作者：
Serpell LC
DOI：
10.3390/antiox11061088
发表时间：
2022-05-30
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/j.bbadis.2008.06.003
发表时间：
2008-09-01
影响因子：
6.2
作者：
Chafekar, Sidhartha M.;Baas, Frank;Scheper, Wiep
通讯作者：
Scheper, Wiep
针对适当的淀粉样β神经元毒素：阿尔茨海默病免疫治疗的前进之路。
DOI：
10.1186/alzrt272
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Goure WF;Krafft GA;Jerecic J;Hefti F
通讯作者：
Hefti F