The binding of apolipoprotein E to oligomers and fibrils of amyloid-β alters the kinetics of amyloid aggregation.
The binding of apolipoprotein E to oligomers and fibrils of amyloid-β alters the kinetics of amyloid aggregation.
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DOI：
10.1021/bi5008172
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发表时间：
2014-10-14
期刊：
影响因子：
2.9
通讯作者：
Frieden, Carl
中科院分区：
文献类型：
--
作者：
Garai, Kanchan;Verghese, Philip B.;Baban, Berevan;Holtzman, David M.;Frieden, Carl
阿尔茨海默病（AD）中淀粉样蛋白-β (Aβ)沉积与APOE基因型密切相关。然而，载脂蛋白E （apoE）在Aβ聚集中的作用仍不清楚。在这里，我们使用不同的apoE制剂，如重组蛋白或从培养的星形胶质细胞中分离的蛋白，来研究apoE对Aβ1-40和Aβ1-42聚集的影响。通过四甲基罗丹明标记的Aβ的荧光损失来测量的聚集动力学显示，载脂蛋白e的亚化学计量浓度的存在显着减慢了聚集动力学。使用这些浓度，我们得出结论，apoE主要结合并影响低聚物的生长，从而导致原纤维生长所需的细胞核。在较高的apoE浓度下，该蛋白也与a β原纤维结合，导致原纤维稳定和纤维生长速度减慢。a - β1 - 40的聚集依赖于apoE亚型，在apoE4中最明显，而在apoE3和apoE2中则不那么明显。我们的研究结果表明，apoE4在AD中的有害作用可能与apoe诱导的可溶性但具有细胞毒性的Aβ寡聚物形式和中间体的稳定以及纤维的稳定有关。
Deposition of amyloid-β (Aβ) in Alzheimer’s disease (AD) is strongly correlated with the APOE genotype. However, the role of apolipoprotein E (apoE) in Aβ aggregation has remained unclear. Here we have used different apoE preparations, such as recombinant protein or protein isolated from cultured astrocytes, to examine the effect of apoE on the aggregation of both Aβ1–40 and Aβ1–42. The kinetics of aggregation, measured by the loss of fluorescence of tetramethylrhodamine-labeled Aβ, is shown to be dramatically slowed by the presence of substoichiometric concentrations of apoE. Using these concentrations, we conclude that apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth. At higher apoE concentrations, the protein also binds to Aβ fibrils, resulting in fibril stabilization and a slower rate of fibril growth. The aggregation of Aβ1–40 is dependent on the apoE isoform, being the most dramatic for apoE4 and less so for apoE3 and apoE2. Our results indicate that the detrimental role of apoE4 in AD could be related to apoE-induced stabilization of the soluble but cytotoxic oligomeric forms and intermediates of Aβ, as well as fibril stabilization.
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DOI：
10.1523/jneurosci.0033-12.2012
发表时间：
2012-04-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bien-Ly N;Gillespie AK;Walker D;Yoon SY;Huang Y
通讯作者：
Huang Y
影响因子：
4.8
作者：
Cerf, Emilie;Gustot, Adelin;Raussens, Vincent
通讯作者：
Raussens, Vincent
影响因子：
1.7
作者：
Beffert, U;Poirier, J
通讯作者：
Poirier, J
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
2.9
作者：
Garai, Kanchan;Baban, Berevan;Frieden, Carl
通讯作者：
Frieden, Carl