Complicated function of dopamine in A beta-related neurotoxicity: Dual interactions with Tyr(10) and SNK(26-28) of A beta
Complicated function of dopamine in A beta-related neurotoxicity: Dual interactions with Tyr(10) and SNK(26-28) of A beta
复制标题
多巴胺在 Aβ 相关神经毒性中的复杂功能：与 Aβ 的 Tyr(10) 和 SNK(26-28) 的双重相互作用
DOI：
10.1016/j.jinorgbio.2016.09.007
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发表时间：
2016
影响因子：
3.9
通讯作者：
Xiang Juan
中科院分区：
文献类型：
--
作者：
Liu Mengmeng;Kou Lu;Bin Yannan;Wan Liping;Xiang Juan
多巴胺（DA）和其他儿茶酚衍生物具有抑制β淀粉样肽（Aβ）原纤维形成的能力，被认为是治疗阿尔茨海默病（AD）的潜在药物。然而，由于Aβ和DA在AD病理中的不同功能，这种治疗仍然存在争议。此外，DA伴随的复杂氧化使得以往的研究大多集中在DA氧化物与Aβ的结合上。与脑功能相关的Aβ与DA还原态相互作用的分子机制亟待探讨。通过控制严格的厌氧实验条件，研究了Aβ/DA相互作用的分子机制，发现了两个结合位点。对于DA的结合，酪氨酸（Tyr10）被鉴定为强结合位点，丝氨酸-天冬氨酸裂解（SNK(26-28)）片段为弱结合位点。此外，硫黄素T （THT）荧光通过与SNK（26-28）片段的弱结合证实了DA抑制Aβ聚集的积极作用。同时，7-OHCCA荧光表现出DA通过抑制Aβ/Cu2 +配位促进自由基dotOH生成的负功能。神经母细胞瘤SH-SY5Y细胞的活力测试显示，DA、Cu2 +和Aβ共存诱导的细胞活力低于游离Cu2 +，表明过量DA对AD进展有显著的负面影响。本研究揭示了DA在AD大脑中潜在的损伤，这对于理解DA在AD神经病理中的作用以及设计DA相关的AD治疗策略具有重要意义。
With the capability to inhibit the formation of amyloid β peptides (Aβ) fibril, dopamine (DA) and other catechol derivatives have been considered for the potential treatment of Alzheimer's disease (AD). Such treatment, however, remains debatable because of the diverse functions of Aβ and DA in AD pathology. Moreover, the complicated oxidation accompanying DA has caused the majority of the previous research to focus on the binding of DA oxides onto Aβ. The molecular mechanism by which Aβ interacts with the reduction state of DA, which is correlative with the brain function, should be urgently explored. By controlling rigorous anaerobic experimental conditions, this work investigated the molecular mechanism of the Aβ/DA interaction, and two binding sites were revealed. For the binding of DA, Tyrosine (Tyr10) was identified as the strong binding site, and serine-asparagine-lysing (SNK(26–28)) segment was the weak binding segment. Furthermore, the Thioflavin T (THT) fluorescence confirmed DA's positive function of inhibiting Aβ aggregation through its weakly binding with SNK(26–28) segment. Meanwhile, 7-OHCCA fluorescence exhibited DA's negative function of enhancing radical dotOH generation through inhibiting the Aβ/Cu2 +coordination. The viability tests of the neuroblastoma SH-SY5Y cells displayed that the coexistence of DA, Cu2 +, and Aβ induced lower cell viability than free Cu2 +, indicating the significant negative effect of excessive DA on AD progression. This research revealed the potential DA-induced damage in AD brain, which is significant for understanding the function of DA in AD neuropathology and for designing a DA-related therapeutic strategy for AD.