CE can identify small molecules that selectively target soluble oligomers of amyloid β protein and display antifibrillogenic activity
CE can identify small molecules that selectively target soluble oligomers of amyloid β protein and display antifibrillogenic activity
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DOI：
10.1002/elps.200800377
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发表时间：
2009-04-01
期刊：
影响因子：
2.9
通讯作者：
De Lorenzi, Ersilia
中科院分区：
文献类型：
--
作者：
Colombo, Raffaella;Carofti, Angelo;De Lorenzi, Ersilia
淀粉样β（A β）蛋白的可溶性和毒性寡聚体已被鉴定为参与阿尔茨海默病的真正神经毒性物质，并且将它们视为抑制A β聚集的靶点可能具有治疗价值。我们先前建立了一种CE方法，该方法能够分离和定量沿着导致原纤维的途径的含有42个氨基酸（A β（1-42））的A β蛋白的瞬时寡聚体，并且我们现在展示了这种方法如何成功地应用于检查小分子对A β寡聚化的体外抑制作用。为此，我们研究了米托蒽醌和匹蒽醌，两种著名的抗癌药物，以及苏拉明和苏拉明样化合物。通过使用CE，这里显示了米托蒽醌和匹蒽醌如何减少或阻断A β（1-42）寡聚化，而硫磺素T荧光光谱测定和透射电子显微镜显示了这两种化合物如何也显示抗原纤维生成活性。有趣的是，体外细胞活力实验表明，匹蒽醌显着降低A β（1-42）神经毒性。
Soluble and toxic oligomers of amyloid beta (A beta) protein have been identified as the true neurotoxic species involved in Alzheimer's disease and considering them as targets to inhibit A beta aggregation might have a therapeutic value. We previously set up a CE method that enables the separation and quantification of transient oligomers of A beta protein-containing 42 amino acids (A beta(1-42)) along the pathway leading to fibrils and we now demonstrate how this method can be successfully applied to examine the in vitro inhibitory effects of small molecules on A beta oligomerization. To this end, we investigated mitoxantrone and pixantrone, two well-known anticancer drugs, as well as suramin and a suramin-like compound. By using CE, it is here shown how mitoxantrone and pixantrone either reduce or block A beta(1-42) oligomerization, while Thioflavin T spectrofluorimetric assay and transmission electron microscopy demonstrate how these two compounds also display antifibrillogenic activity. Interestingly, in vitro cell viability experiments indicated that pixantrone significantly reduces A beta(1-42) neurotoxicity.