A central role for dityrosine crosslinking of Amyloid-β in Alzheimer's disease.
A central role for dityrosine crosslinking of Amyloid-β in Alzheimer's disease.
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DOI：
10.1186/2051-5960-1-83
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发表时间：
2013-12-18
影响因子：
7.1
通讯作者：
Serpell LC
中科院分区：
文献类型：
--
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
阿尔茨海默病（Alzheimer's disease，AD）的特征是在由高度稳定的自组装β-淀粉样蛋白（Amyloid-beta，Aβ）纤维组成的神经元中沉积不溶性淀粉样蛋白斑块。铜被认为在阿尔茨海默病中起作用。已从AD脑中分离出Aβ二聚体，并已证明其具有神经毒性。我们研究了在高铜氧化应激条件下两个酪氨酸残基共价邻位-邻位偶联形成的Aβ42中双酪氨酸交联的形成，并表明双酪氨酸可在体外Aβ寡聚体和原纤维中形成，这些连接进一步稳定了原纤维。通过免疫金标记透射电子显微镜观察，在用寡聚体Aβ42处理的细胞培养物中，使用双酪氨酸特异性抗体在内化Aβ中存在双酪氨酸交联。结果还揭示了AD患者脑组织和脑脊液中淀粉样斑块中双酪氨酸交联的患病率。Aβ二聚体可通过二酪氨酸交联来稳定。这些结果表明，双酪氨酸交联可能在阿尔茨海默病的发病机制中起着重要作用，可以由活性氧簇催化的Cu 2+离子产生。AD患者CSF中Aβ和二酪氨酸增加的观察结果表明，这可用作AD中氧化应激的潜在生物标志物。
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.
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DOI：
10.1073/pnas.0904532106
发表时间：
2010-02-02
影响因子：
11.1
作者：
Friedrich, Ralf P.;Tepper, Katharina;Faendrich, Marcus
通讯作者：
Faendrich, Marcus
DOI：
10.1196/annals.1306.012
发表时间：
2004-01-01
期刊：
REDOX-ACTIVE METALS IN NEUROLOGICAL DISORDERS
影响因子：
--
作者：
Huang, XD;Moir, RD;Rogers, JT
通讯作者：
Rogers, JT
影响因子：
4
作者：
Agholme, Lotta;Hallbeck, Martin;Kagedal, Katarina
通讯作者：
Kagedal, Katarina
影响因子：
4.8
作者：
Curtain, CC;Ali, F;Barnham, KJ
通讯作者：
Barnham, KJ
DOI：
10.1016/s0378-4347(97)00248-x
发表时间：
1997-08-29
期刊：
JOURNAL OF CHROMATOGRAPHY B
影响因子：
--
作者：
Abdelrahim, M;Morris, E;Verma, A
通讯作者：
Verma, A