Suppression of Oligomer Formation and Formation of Non-Toxic Fibrils upon Addition of Mirror-Image Aβ42 to the Natural l-Enantiomer.
Suppression of Oligomer Formation and Formation of Non-Toxic Fibrils upon Addition of Mirror-Image Aβ42 to the Natural l-Enantiomer.
复制标题
DOI：
10.1002/anie.201706279
复制
发表时间：
2017-09-11
期刊：
影响因子：
--
通讯作者：
Raskatov JA
中科院分区：
文献类型：
--
作者：
Dutta S;Foley AR;Warner CJA;Zhang X;Rolandi M;Abrams B;Raskatov JA
外消旋体的溶解度通常低于对映不纯化合物，对映体的混合可以增强肽的聚集倾向。淀粉样蛋白β (a β) 42是一种易于聚集的肽，被认为在阿尔茨海默病中起关键作用。可溶性Aβ42聚集中间体（低聚物）具有特别的神经毒性。我们假设镜像（D-） Aβ42的加入可以降低天然（L-） Aβ42形成的有毒低聚物的浓度。我们合成了L-和d - a - β42，发现它们的等摩尔混合可以加速纤维的形成。荧光标记对映异构体类似物的共聚焦显微镜显示它们在外消旋原纤维中共定位。外消旋Aβ42不容易形成可溶性低聚物，这反映了增强的纤维形成倾向。这导致细胞免受L-Aβ42浓度高达50µM的毒性的保护。综上所述，Aβ42对映体的混合诱导了无毒原纤维的加速形成。我们合成了Aβ42的两种对映体，并发现它们的混合能显著加速成纤维。当由荧光标记的类似物制成时，外消旋原纤维显示出对映异构体的高度共定位。外消旋体产生低聚体聚集中间体的倾向降低，显著抑制了天然l - a - β42对映体的毒性。
Racemates often have lower solubility than enantiopure compounds, and mixing of enantiomers can enhance aggregation propensity of peptides. Amyloid β (Aβ) 42 is an aggregation-prone peptide, believed to play a key role in Alzheimer’s Disease. Soluble Aβ42 aggregation intermediates (oligomers) have emerged as particularly neurotoxic. We hypothesized that addition of mirror image (D-) Aβ42 should reduce the concentration of toxic oligomers formed by natural (L-) Aβ42. We synthesized L- and D-Aβ42 and found their equimolar mixing to lead to accelerated fibril formation. Confocal microscopy with fluorescently labeled analogs of the enantiomers showed their co-localization in racemic fibrils. Reflecting enhanced fibril formation propensity, racemic Aβ42 was less prone to form soluble oligomers. This resulted in protection of cells from toxicity of L-Aβ42 at concentrations ranging up to 50 µM. In summary, mixing of Aβ42 enantiomers induces accelerated formation of non-toxic fibrils. We synthesized both enantiomers of Aβ42 and found their mixing to induce drastic acceleration of fibrillization. When made from fluorescently labelled analogues, racemic fibrils showed high degree of co-localization of the enantiomers. The racemate showed a reduced propensity to yield oligomeric aggregation intermediates, which, remarkably, resulted in inhibition of toxicity of the natural L-Aβ42 enantiomer in the racemate.
登录
查看更多内容
影响因子：
8.4
作者：
Raskatov, Jevgenij A.;Thompson, Amber L.;Brown, John M.
通讯作者：
Brown, John M.
影响因子：
4.2
作者：
Ciccotosto, Giuseppe D.;Tew, Deborah J.;Cappai, Roberto
通讯作者：
Cappai, Roberto
影响因子：
4.8
作者：
Ghanta, J;Shen, CL;Murphy, RM
通讯作者：
Murphy, RM
影响因子：
14.8
作者：
Bieschke, Jan;Herbst, Martin;Wanker, Erich E.
通讯作者：
Wanker, Erich E.
DOI：
10.1073/pnas.1600749113
发表时间：
2016-08-23
影响因子：
11.1
作者：
Walti, Marielle Aulikki;Ravotti, Francesco;Riek, Roland
通讯作者：
Riek, Roland