Section of Cell Biology and Biophysics, Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15701, Greece.
Int J Mol Sci. 2019 May 8;20(9):2274. doi: 10.3390/ijms20092274.
Human apolipoprotein E (apoE) is a major component of lipoprotein particles, and under physiological conditions, is involved in plasma cholesterol transport. Human apolipoprotein E found in three isoforms (E2; E3; E4) is a member of a family of apolipoproteins that under pathological conditions are detected in extracellular amyloid depositions in several amyloidoses. Interestingly, the lipid-free apoE form has been shown to be co-localized with the amyloidogenic Aβ peptide in amyloid plaques in Alzheimer's disease, whereas in particular, the apoE4 isoform is a crucial risk factor for late-onset Alzheimer's disease. Evidence at the experimental level proves that apoE self-assembles into amyloid fibrilsin vitro, although the misfolding mechanism has not been clarified yet. Here, we explored the mechanistic insights of apoE misfolding by testing short apoE stretches predicted as amyloidogenic determinants by AMYLPRED, and we computationally investigated the dynamics of apoE and an apoE-Αβ complex. Our in vitro biophysical results prove that apoE peptide-analogues may act as the driving force needed to trigger apoE aggregation and are supported by the computational apoE outcome. Additional computational work concerning the apoE-Αβ complex also designates apoE amyloidogenic regions as important binding sites for oligomeric Αβ; taking an important step forward in the field of Alzheimer's anti-aggregation drug development.
人载脂蛋白 E（apoE）是脂蛋白颗粒的主要成分，在生理条件下，参与血浆胆固醇转运。人载脂蛋白 E 有三种异构体（E2；E3；E4），是载脂蛋白家族的一员，在几种淀粉样变性病中，在细胞外淀粉样沉积物中检测到病理条件下的载脂蛋白 E。有趣的是，无脂载脂蛋白 E 形式已被证明与阿尔茨海默病淀粉样斑块中的淀粉样生成 Aβ肽共定位，而特别是 apoE4 异构体是晚发性阿尔茨海默病的关键危险因素。实验水平的证据证明 apoE 在体外自组装成淀粉样纤维，尽管错误折叠机制尚未阐明。在这里，我们通过测试 AMYLPRED 预测的作为淀粉样蛋白决定因素的短 apoE 片段，探索了 apoE 错误折叠的机制见解，并且我们通过计算研究了 apoE 和 apoE-Aβ 复合物的动力学。我们的体外生物物理结果证明 apoE 肽类似物可能作为触发 apoE 聚集所需的驱动力，并且得到了计算 apoE 结果的支持。关于 apoE-Aβ 复合物的额外计算工作还将 apoE 淀粉样变性区域指定为寡聚 Aβ的重要结合位点；在阿尔茨海默病抗聚集药物开发领域迈出了重要的一步。
