High ability of apolipoprotein E4 to stabilize amyloid-β peptide oligomers, the pathological entities responsible for Alzheimer's disease
High ability of apolipoprotein E4 to stabilize amyloid-β peptide oligomers, the pathological entities responsible for Alzheimer's disease
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DOI：
10.1096/fj.10-175976
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发表时间：
2011-05-01
期刊：
影响因子：
4.8
通讯作者：
Raussens, Vincent
中科院分区：
文献类型：
--
作者：
Cerf, Emilie;Gustot, Adelin;Raussens, Vincent
如今，淀粉样β蛋白(Aβ)寡聚体在阿尔茨海默病(AD)中的新角色已被广泛接受，抛开了纤维是导致疾病发生的主要实体的旧观念。此外，携带载脂蛋白E(ApoE)的E4亚型代表着发生AD的最高风险。然而，载脂蛋白E4在AD中的参与仍然是令人困惑的。这项研究的目的是为apoE4在Aβ聚集中的作用带来新的见解。我们使用红外光谱、硫代黄素T荧光和Western blots来评估载脂蛋白E亚型对体外Aβ聚集的影响。将Aβ对照组与与apoE3或apoE4亚型孵育的Aβ进行比较，我们报告Aβ纤维含量减少了30%，而与病理亚型apoE4孵育的低聚物含量高出2倍。ApoE4会在其寡聚构象中结合和阻断Aβ，抑制毒性较低的Aβ纤维形式的进一步形成。虽然以前的研究大多将E4与纤维联系在一起，但我们的报告强调了apoE4和Aβ寡聚体之间的联系，因此将apoE4与新的淀粉样级联假说相一致。-Cerf，E.，Gustot，A.，Goormaghtigh，E.，Ruysschaert，J.-M.，Raussens，V.载脂蛋白E4稳定淀粉样β多肽寡聚体的高能力，这是导致阿尔茨海默病的病理实体。FASE B J.25,1585-1595(2011)。Www.fasebj.org
Nowadays, the emerging role of amyloid-beta peptide (A beta) oligomers in Alzheimer's disease (AD) is widely accepted, putting aside the old idea that fibrils are the primary entities responsible for the onset of the disease. Besides, carrying the E4 isoform of apolipoprotein E (apoE) represents the highest risk of developing AD. Nevertheless, the involvement of apoE4 in AD remains confusing. The goal of this study was to bring new insights into the role of apoE4 in A beta aggregation. We used infrared spectroscopy, thioflavin T fluorescence, and Western blots to evaluate the influence of apoE isoforms on A beta aggregation in vitro. Comparing A beta controls with A beta incubated either with the apoE3 or apoE4 isoform, we report a 30% reduction of the A beta fibrillar content, whereas the oligomeric content is 2 times higher on incubation with the pathological isoform apoE4. ApoE4 would bind and block A beta in its oligomeric conformation, inhibiting further formation of less toxic fibrillar forms of A beta. While previous studies mostly correlated E4 with fibrils, our report underlines a link between apoE4 and A beta oligomers and therefore reconciles apoE4 with the new amyloid cascade hypothesis. Our observations suggest that apoE4 strongly stabilizes A beta oligomers, the pathological species responsible for Alzheimer's disease.-Cerf, E., Gustot, A., Goormaghtigh, E., Ruysschaert, J.-M., Raussens, V. High ability of apolipoprotein E4 to stabilize amyloid-beta peptide oligomers, the pathological entities responsible for Alzheimer's disease. FASEB J. 25, 1585-1595 (2011). www.fasebj.org