Steady, Symmetric, and Reversible Growth and Dissolution of Individual Amyloid-β Fibrils
Steady, Symmetric, and Reversible Growth and Dissolution of Individual Amyloid-β Fibrils
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DOI：
10.1021/acschemneuro.9b00179
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发表时间：
2019-06-01
影响因子：
5
通讯作者：
Vekilov, Peter G.
中科院分区：
文献类型：
--
作者：
Xu, Yuechuan;Safari, Mohammad S.;Vekilov, Peter G.
淀粉样蛋白- β (A β)肽的低聚物和原纤维与阿尔茨海默病的病理有关。在这里，我们通过时间分辨原位原子力显微镜监测单个A β 40原纤维的生长，从而直接测量原纤维的生长速率。在包括单个原丝和成束原丝的原纤维群体中，测量的生长速率与原丝的厚度无关，这表明相邻原丝之间的合作不影响单体的结合。单个原纤维的两端以相似的速率生长。与之前观察到的淀粉样蛋白形成肽的“走走停停”动力学相反，在0-10 μ m的肽浓度下，A β 40原纤维的生长和溶解相对稳定。原纤维很容易在静止的无肽溶液中溶解，其速率与生长和溶解的微观可变性相一致。重要的是，单体与纤维末端结合的双分子速率系数明显小于扩散极限，这意味着单体与纤维结合的过渡态具有相对较高的自由能。
Oligomers and fibrils of the amyloid-beta (A beta) peptide are implicated in the pathology of Alzheimer's disease. Here, we monitor the growth of individual A beta 40 fibrils by time-resolved in situ atomic force microscopy and thereby directly measure fibril growth rates. The measured growth rates in a population of fibrils that includes both single protofilaments and bundles of filaments are independent of the fibril thickness, indicating that cooperation between adjacent protofilaments does not affect incorporation of monomers. The opposite ends of individual fibrils grow at similar rates. In contrast to the "stop-and-go" kinetics that has previously been observed for amyloid-forming peptides, growth and dissolution of the A beta 40 fibrils are relatively steady for peptide concentration of 0-10 mu M. The fibrils readily dissolve in quiescent peptide-free solutions at a rate that is consistent with the microscopic reversibility of growth and dissolution. Importantly, the bimolecular rate coefficient for the association of a monomer to the fibril end is significantly smaller than the diffusion limit, implying that the transition state for incorporation of a monomer into a fibril is associated with a relatively high free energy.