School of Life Sciences, University of Sussex, Falmer BN1 9QG, UK.
Acta Neuropathol Commun. 2013 Dec 18;1:83. doi: 10.1186/2051-5960-1-83.
Alzheimer's disease (AD) is characterized by the deposition of insoluble amyloid plaques in the neuropil composed of highly stable, self-assembled Amyloid-beta (Aβ) fibrils. Copper has been implicated to play a role in Alzheimer's disease. Dimers of Aβ have been isolated from AD brain and have been shown to be neurotoxic.
We have investigated the formation of dityrosine cross-links in Aβ42 formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress with elevated copper and shown that dityrosine can be formed in vitro in Aβ oligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized Aβ in cell cultures treated with oligomeric Aβ42 using a specific antibody for dityrosine by immunogold labeling transmission electron microscopy. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and in cerebrospinal fluid from AD patients.
Aβ dimers may be stabilized by dityrosine crosslinking. These results indicate that dityrosine cross-links may play an important role in the pathogenesis of Alzheimer's disease and can be generated by reactive oxygen species catalyzed by Cu2+ ions. The observation of increased Aβ and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD.
阿尔茨海默病（AD）的特征是神经突中不溶性淀粉样斑块的沉积，由高度稳定的、自组装的β淀粉样蛋白（Aβ）纤维组成。铜已被牵连在阿尔茨海默病中发挥作用。二聚体的 Aβ 已从 AD 大脑中分离出来，并已被证明具有神经毒性。
我们研究了在氧化应激条件下，通过两个酪氨酸残基的共价邻-邻偶联形成的 Aβ42 中二酪氨酸交联的形成，结果表明二酪氨酸可以在体外 Aβ 低聚物和原纤维中形成，并且这些键进一步稳定了原纤维。在使用针对二酪氨酸的特异性抗体通过免疫金标记透射电子显微镜对用寡聚 Aβ42 处理的细胞培养物中的内化 Aβ 进行研究时，发现了二酪氨酸交联。结果还揭示了二酪氨酸交联在脑组织中的淀粉样斑块中和 AD 患者的脑脊液中普遍存在。
Aβ 二聚体可能通过二酪氨酸交联稳定。这些结果表明，二酪氨酸交联可能在阿尔茨海默病的发病机制中起重要作用，并且可以由 Cu2+ 离子催化的活性氧物种产生。从 AD 患者的 CSF 中观察到 Aβ 和二酪氨酸的增加表明，这可以用作 AD 中氧化应激的潜在生物标志物。
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