Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain
Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain
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DOI：
10.1093/brain/awz066
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发表时间：
2019-05-01
期刊：
影响因子：
14.5
通讯作者：
Walsh, Dominic M.
中科院分区：
文献类型：
--
作者：
Brinkmalm, Gunnar;Hong, Wei;Walsh, Dominic M.
经典淀粉样β蛋白的一级结构在30多年前就被阐明，但在阿尔茨海默病发病机制中起作用的淀粉样β蛋白的形式仍然不清楚。对阿尔茨海默氏病脑提取物的研究表明，在十二烷基硫酸钠聚丙烯酰胺凝胶电泳上迁移的分子量类似于7 kDa（7 kDa-A β）的淀粉样蛋白-β特别有毒;然而，该物种的性质一直存在争议。使用复杂的质谱和灵敏的疾病相关毒性测定，我们表明，脑源性生物活性7 kDa-A β含有共价交联的二聚体的异质混合物，在没有任何其他可检测的蛋白质。淀粉样蛋白β二聚体的鉴定可能会开启阿尔茨海默病研究的新阶段，并使人们更好地了解阿尔茨海默病，以及如何监测和治疗这种毁灭性的疾病。未来的研究调查在已知位点交联的个体二聚体的生物活性将是这一努力的关键。
The primary structure of canonical amyloid-beta-protein was elucidated more than 30 years ago, yet the forms of amyloid-beta that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-beta, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of similar to 7 kDa (7kDa-A beta), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-A beta contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-beta dimers may open a new phase of Alzheimer's research and allow a better understanding of Alzheimer's disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.