Methylene blue inhibits amyloid Aβ oligomerization by promoting fibrillization
Methylene blue inhibits amyloid Aβ oligomerization by promoting fibrillization
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DOI：
10.1021/bi700411k
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发表时间：
2007-07-31
期刊：
影响因子：
2.9
通讯作者：
Glabe, Charles G.
中科院分区：
文献类型：
--
作者：
Necula, Mihaela;Breydo, Leonid;Glabe, Charles G.
淀粉样斑块是阿尔茨海默病的标志性神经病理学病变，其由异常聚集的A β蛋白组成。已鉴定出多种A β聚集物质，神经毒性似乎与非纤维状低聚物的量相关。因此，选择性抑制A β寡聚体形成已成为一种有吸引力的治疗干预手段。为了研究小分子是否可以调节聚集以实现神经毒性淀粉样蛋白寡聚体的选择性抑制，在亚甲蓝存在下，使用免疫反应性与前原纤维寡聚体特异性抗体A11，透射电子显微镜和浊度测定法在体外测定A β聚集。亚甲基蓝抑制寡聚化时，在亚化学计量浓度相对于A β单体。A β寡聚化的抑制与纤维化的促进同时实现，表明寡聚体和原纤维形成是不同的竞争途径。亚甲基蓝介导的促进纤维形成发生通过剂量依赖性的减少滞后时间和增加的纤维化率，与促进长丝成核和伸长一致。加入亚甲蓝预聚物导致低聚物损失和促进纤维化。数据显示，通过促进原纤维形成来抑制A β寡聚体形成，这表明可以使用亚甲蓝在体内测试寡聚体和原纤维的相对病理学意义。如果A β寡聚体代表主要致病物质，则通过促进毒性较小的聚集体的形成来抑制这种高毒性物质可能在治疗上有用。
Amyloid plaques are hallmark neuropathological lesions in Alzheimer's disease, which consist of abnormally aggregated A beta protein. Multiple A beta aggregated species have been identified, and neurotoxicity appears to be correlated with the amount of nonfibrillar oligomers. Therefore, selective inhibition of A beta oligomer formation has emerged as an attractive means of therapeutic intervention. To investigate whether small molecules can modulate aggregation to achieve selective inhibition of neurotoxic amyloid oligomers, A beta aggregation was assayed in vitro in the presence of methylene blue, using immunoreactivity with the prefibrillar oligomer-specific antibody A11, transmission electron microscopy, and turbidity assays. Methylene blue inhibited oligomerization when used at substoichiometric concentrations relative to that of the A beta monomer. Inhibition of A beta oligomerization was achieved concomitant with promotion of fibrillization, suggesting that oligomer and fibril formation are distinct and competing pathways. Methylene blue-mediated promotion of fiber formation occurred via a dose-dependent decrease in the lag time and an increase in the fibrillization rate, consistent with promotion of both filament nucleation and elongation. Addition of methylene blue to preformed oligomers resulted in oligomer loss and promotion of fibrillization. The data show that A beta oligomer formation is inhibited by promoting fibril formation, which suggests that the relative pathological significance of oligomers and fibrils may be tested in vivo using methylene blue. If A beta oligomers represent the primary pathogenic species, then inhibition of this highly toxic species via promotion of formation of less toxic aggregates may be therapeutically useful.