Copper Enhances Amyloid-β Peptide Neurotoxicity and non β-Aggregation: A Series of Experiments Conducted upon Copper-Bound and Copper-Free Amyloid-β Peptide
Copper Enhances Amyloid-β Peptide Neurotoxicity and non β-Aggregation: A Series of Experiments Conducted upon Copper-Bound and Copper-Free Amyloid-β Peptide
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DOI：
10.1007/s12031-009-9282-8
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发表时间：
2010-05-01
影响因子：
3.1
通讯作者：
Jiang, Zhaofeng
中科院分区：
文献类型：
--
作者：
Dai, Xueling;Sun, Yaxuan;Jiang, Zhaofeng
阿尔茨海默病的特征在于淀粉样β肽（A β）在细胞外沉积物（称为老年斑）中的异常聚集。然而，毒性A β物质的性质及其确切的作用机制仍不清楚。以往的研究表明组氨酸残基参与了铜与A β的相互作用，从而导致A β的神经毒性和自由基损伤。在这里，我们采用了一种突变体A β（A β H13 R），其中组氨酸残基被精氨酸取代。铜促进沉淀的野生型和突变体A β在分光光度法吸光度测定，但抑制β-结构聚集体根据硫代嘌呤-T测定。单独的野生型A β比A β H13 R-铜络合物具有更强的细胞毒性，但产生的H2 O2量更少，表明A β-膜相互作用也可能与病理进展有关。尽管聚集体主要由非β原纤维物质组成，但β毒性与其聚集能力呈正相关。总之，这些发现可能为铜在阿尔茨海默病发病机制中的作用提供进一步的证据。
Alzheimer's disease is characterized by the abnormal aggregation of amyloid-beta peptide (A beta) in extracellular deposits known as senile plaques. However, the nature of the toxic A beta species and its precise mechanism of action remain unclear. Previous reports suggest that the histidine residues are involved in copper-A beta interaction, by which resulting in the neurotoxicity of A beta and free radical damage. Here, we employed a mutant A beta (A beta H13R) in which a histidine residue was replaced by arginine. Copper facilitated the precipitation of both wild-type and mutant A beta in the spectrophotometric absorbance assay but suppressed beta-structure aggregates according to Thioflavine-T assay. Wild-type A beta alone is more cytotoxic but produced less amount of H2O2 than A beta H13R-copper complexes, suggesting that A beta-membrane interaction may also implicated in the pathologic progress. A beta toxicity is in positive correlation to its competence to aggregate despite the aggregation is mainly composed of non-beta fibril substances. In short, these findings may provide further evidence on the role of copper in the pathogenesis of Alzheimer's disease.