Noy Dror, Solomonov Inna, Sinkevich Ory, Arad Talmon, Kjaer Kristian, Sagi Irit
Structural Biology Department and Electron Microscopy Unit, Weizmann Institute of Science, Rehovot 76100, Israel.
J Am Chem Soc. 2008 Jan 30;130(4):1376-83. doi: 10.1021/ja076282l. Epub 2008 Jan 8.
The role of zinc, an essential element for normal brain function, in the pathology of Alzheimer's disease (AD) is poorly understood. On one hand, physiological and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid beta-protein (Abeta) in senile plaques. On the other hand, levels of extracellular ("free") zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing Abeta aggregation. Remarkably, the release of transient high local concentrations of zinc during rapid synaptic events was reported. The role of such free zinc pulses in promoting Abeta aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concentrations, immediately interacts with Abeta 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of Abeta fibrils (more benign species) presumably by interfering with the self-assembly process of Abeta. These in vitro results strongly suggest a significant role for zinc pulses in Abeta pathology. We further propose that by interfering with Abeta self-assembly, which leads to insoluble, non-pathological fibrillar forms, zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of molecular pathogens that effectively perturb the self-assembly of benign Abeta fibrils, and stabilize harmful non-fibrillar forms.
锌作为正常脑功能所必需的元素，其在阿尔茨海默病（AD）病理过程中的作用仍知之甚少。一方面，来自转基因小鼠模型的生理学和遗传学证据支持其在促进老年斑中β-淀粉样蛋白（Aβ）沉积方面的致病作用。另一方面，根据脑脊液中的锌水平推断，脑中细胞外（“游离”）锌的水平过低，不足以诱导Aβ聚集。值得注意的是，有报道称在快速突触事件期间会释放短暂的高局部浓度锌。这种游离锌脉冲在促进Aβ聚集方面的作用尚未得到证实。我们使用一系列时间分辨的结构和光谱技术发现，当以微摩尔浓度的毫秒脉冲形式引入锌时，它会立即与Aβ1-40相互作用并促进其聚集。这些相互作用特异性地稳定了与非纤维状致病相关的聚集形式，并可能通过干扰Aβ的自组装过程来阻止Aβ纤维（更良性的形式）的形成。这些体外结果强烈表明锌脉冲在Aβ病理过程中起着重要作用。我们进一步提出，通过干扰导致不溶性、非病理性纤维状形式的Aβ自组装，锌稳定了短暂的有害淀粉样蛋白形式。本报告认为，锌代表了一类分子病原体，它们有效地扰乱了良性Aβ纤维的自组装，并稳定了有害的非纤维状形式。
