Copper abolishes the beta-sheet secondary structure of preformed amyloid fibrils of amyloid-beta(42).
Copper abolishes the beta-sheet secondary structure of preformed amyloid fibrils of amyloid-beta(42).
复制标题
DOI：
10.3233/jad-2009-1235
复制
发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Exley C
中科院分区：
文献类型：
--
作者：
House E;Mold M;Collingwood J;Baldwin A;Goodwin S;Exley C
在阿尔茨海默病的脑组织中观察到金属和淀粉样蛋白42(Aβ42，Aβ42)的共沉积，促使人们对金属在这种多肽的沉淀中所起的作用进行了无数的研究。铜被单体Aβ42结合，在铜-多肽络合物沉淀时，从而阻止Aβ42采用β-Sheet二级结构。铜也被Aβ-Sheet构象的Aβ42结合，在这里我们研究了这种相互作用如何影响沉淀肽的构象。铜显著降低了老化的纤维状Aβ42的硫黄素T荧光，例如，金属过量20倍，导致硫黄素T荧光减少约90%。透射电子显微镜显示，铜显着减少了淀粉样纤维的数量，而刚果红染色和偏振光显示，铜诱导的苹果绿双折射消失。交叉偏振光下的显微镜也首次观察到Aβ42的球晶。这些淀粉样结构的大小和外观被发现与阿尔茨海默病组织中发现的球晶非常相似。这些互补方法的综合结果强烈表明，铜取消了预先形成的、老化的Aβ42淀粉样纤维的β-Sheet二级结构。在体内，铜可能对Aβ-Sheet of Aβ42的存在具有保护作用，它与Aβ42纤维的结合可能对阿尔茨海默病的治疗有意义。
The observation of the co-deposition of metals and amyloid-β42 (Aβ42) in brain tissue in Alzheimer’s disease prompted myriad investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric Aβ42 and upon precipitation of the copper-peptide complex thereby prevents Aβ42 from adopting a β-sheet secondary structure. Copper is also bound by β-sheet conformers of Aβ42, and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar Aβ42 with, for example, a 20-fold excess of the metal resulting in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of Aβ42. The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer’s disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the β-sheet secondary structure of pre-formed, aged amyloid fibrils of Aβ42. Copper may protect against the presence of β-sheets of Aβ42 in vivo, and its binding by fibrillar Aβ42 could have implications for Alzheimer’s disease therapy.