Zinc-induced Alzheimer's A beta 1-40 aggregation is mediated by conformational factors
Zinc-induced Alzheimer's A beta 1-40 aggregation is mediated by conformational factors
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DOI：
10.1074/jbc.272.42.26464
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发表时间：
1997-10-17
影响因子：
4.8
通讯作者：
Bush, AI
中科院分区：
文献类型：
--
作者：
Huang, XD;Atwood, CS;Bush, AI
在阿尔茨海默病中，在大脑皮层中积累的A β的异质沉淀物具有不同程度的再溶解抗性。我们以前发现，A β 1-40在体外通过生理浓度的锌快速沉淀，锌是一种神经化学物质，在A β最有可能沉淀的脑区室中非常丰富。我们现在提出的证据表明，锌诱导的A β沉淀是由肽二聚体介导的，并有利于促进α-螺旋和减少β-折叠构象的条件。合成肽溶解的方式对其体外行为至关重要。锌诱导的A β聚集依赖于NaCl的存在，当肽储备溶液冷冻储存时增强。由锌诱导的A β聚集体通过螯合作用是可逆的，但随后可以通过锌再沉淀几个循环，表明肽的构象可能在锌介导的组装中被保留。相反，通过将pH环境恢复至7.4，由低pH（5.5）诱导的A β聚集体不会再溶解。锌-A β相互作用表现出类似于锌介导的纤维蛋白组装的凝胶化过程的特征，这表明，在凝块形成或损伤等事件中，可逆的A β组装可能具有生理目的。这种机制在阿尔茨海默氏病弥漫性斑块的早期演变中被考虑，并提出了一种可能的治疗策略，用于使疾病中某些形式的A β存款再溶解。
The heterogeneous precipitates of A beta that accumulate in the brain cortex in Alzheimer's disease possess varying degrees of resistance to resolubilization. We previously found that A beta 1-40 is rapidly precipitated in vitro by physiological concentrations of zinc, a neurochemical that is highly abundant in brain compartments where A beta is most likely to precipitate. We now present evidence that the zinc-induced precipitation of A beta is mediated by a peptide dimer and favored by conditions that promote alpha-helical and diminish beta-sheet conformations. The manner in which the synthetic peptide is solubilized was critical to its behavior in vitro. Zinc-induced A beta aggregation was dependent upon the presence of NaCl, was enhanced when the peptide stock solution was stored frozen. The A beta aggregates induced by zinc were reversible by chelation, but could then be reprecipitated by zinc for several cycles, indicating that the peptide's conformation is probably preserved in the zinc-mediated assembly. In contrast, A beta aggregates induced by low pH (5.5) were not resolubilized by returning the pH milieu to 7.4. The zinc-A beta interaction exhibits features resembling the gelation process of zinc-mediated fibrin assembly, suggesting that, in events such as clot formation or injury, reversible A beta assembly could be physiologically purposive. Such a mechanism is contemplated in the early evolution of diffuse plaques in Alzheimer's disease and suggests a possible therapeutic strategy for the resolubilization of some forms of A beta deposit in the disease.