Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism
Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism
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DOI：
10.1073/pnas.1218402110
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发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Knowles, Tuomas P. J.
中科院分区：
文献类型：
--
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
在淀粉样蛋白-β（A β）肽A β 42聚集成淀粉样蛋白原纤维和斑块期间产生毒性寡聚体已成为阿尔茨海默病发作和进展的中心特征，但控制病理性聚集的分子途径已被证明具有识别的挑战性。在这里，我们使用动力学研究，选择性放射性标记实验，细胞活力测定的组合，直接检测原纤维和寡聚体的形成率和由此产生的细胞毒性作用。我们的研究结果表明，一旦一个小的，但临界浓度的淀粉样蛋白原纤维已经积累，有毒的低聚物物种主要是由单体肽分子通过原纤维催化的二次成核反应，而不是通过一个经典的机制，均匀的初级成核。这种催化机制将不溶性淀粉样蛋白原纤维的生长和可扩散的寡聚聚集体的产生结合在一起，所述可扩散的寡聚聚集体在阿尔茨海默病中被认为是神经毒性剂。这些结果表明，A β 42的聚集是由一个正反馈环促进的，该正反馈环源于该肽的单体和纤维形式之间的相互作用。我们的研究结果汇集了与A β聚集级联相关的主要分子种类，并表明本研究中确定的次级成核途径的干扰可能是控制神经毒性A β 42低聚物增殖的有效策略。
The generation of toxic oligomers during the aggregation of the amyloid-beta (A beta) peptide A beta 42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer's disease, but the molecular pathways that control pathological aggregation have proved challenging to identify. Here, we use a combination of kinetic studies, selective radiolabeling experiments, and cell viability assays to detect directly the rates of formation of both fibrils and oligomers and the resulting cytotoxic effects. Our results show that once a small but critical concentration of amyloid fibrils has accumulated, the toxic oligomeric species are predominantly formed from monomeric peptide molecules through a fibril-catalyzed secondary nucleation reaction, rather than through a classical mechanism of homogeneous primary nucleation. This catalytic mechanism couples together the growth of insoluble amyloid fibrils and the generation of diffusible oligomeric aggregates that are implicated as neurotoxic agents in Alzheimer's disease. These results reveal that the aggregation of A beta 42 is promoted by a positive feedback loop that originates from the interactions between the monomeric and fibrillar forms of this peptide. Our findings bring together the main molecular species implicated in the A beta aggregation cascade and suggest that perturbation of the secondary nucleation pathway identified in this study could be an effective strategy to control the proliferation of neurotoxic A beta 42 oligomers.