Faculté des Sciences, Aix-Marseille Université, EA4674, Marseille, France.
J Neurochem. 2014 Jan;128(1):186-95. doi: 10.1111/jnc.12390. Epub 2013 Aug 28.
Alzheimer β-amyloid (Aβ) peptides can self-organize into oligomeric ion channels with high neurotoxicity potential. Cholesterol is believed to play a key role in this process, but the molecular mechanisms linking cholesterol and amyloid channel formation have so far remained elusive. Here, we show that the short Aβ22-35 peptide, which encompasses the cholesterol-binding domain of Aβ, induces a specific increase of Ca(2+) levels in neural cells. This effect is neither observed in calcium-free medium nor in cholesterol-depleted cells, and is inhibited by zinc, a blocker of amyloid channel activity. Double mutations V24G/K28G and N27R/K28R in Aβ22-35 modify cholesterol binding and abrogate channel formation. Molecular dynamic simulations suggest that cholesterol induces a tilted α-helical topology of Aβ22-35. This facilitates the establishment of an inter-peptide hydrogen bond network involving Asn-27 and Lys-28, a key step in the octamerization of Aβ22-35 which proceeds gradually until the formation of a perfect annular channel in a phosphatidylcholine membrane. Overall, these data give mechanistic insights into the role of cholesterol in amyloid channel formation, opening up new therapeutic options for Alzheimer's disease. Aβ22-35 peptide, which encompasses the cholesterol binding domain of Aβ, induces a specific increase of Ca(2+) level in neural cells. Double mutations V24G/K28G and N27R/K28R modify cholesterol binding and abrogate channels formation. Molecular dynamic simulations suggest that cholesterol induces a tilted α-helical peptide topology facilitating the formation of annular octameric channels, as schematically shown in the graphic (with a hydrogen bond shown in green for two vicinal peptides). Overall, the data give insights into the role of cholesterol in amyloid channel formation and open up new therapeutic options for Alzheimer's disease.
阿尔茨海默病β-淀粉样蛋白（Aβ）肽可以自组装成具有高神经毒性潜力的寡聚离子通道。胆固醇被认为在这个过程中起关键作用，但将胆固醇与淀粉样通道形成联系起来的分子机制迄今仍不清楚。在这里，我们表明包含 Aβ 胆固醇结合域的短肽 Aβ22-35 诱导神经细胞中 Ca（2+）水平的特异性增加。这种效应在无钙培养基中或胆固醇耗尽的细胞中均观察不到，并且被锌（一种淀粉样通道活性的阻断剂）抑制。Aβ22-35 中的 V24G/K28G 和 N27R/K28R 双突变修饰了胆固醇结合并阻断了通道形成。分子动力学模拟表明胆固醇诱导 Aβ22-35 形成倾斜的 α-螺旋拓扑结构。这有助于建立涉及 Asn-27 和 Lys-28 的肽间氢键网络，这是 Aβ22-35 八聚体形成的关键步骤，该步骤逐渐进行，直到在磷脂膜中形成完美的环形通道。总的来说，这些数据为胆固醇在淀粉样通道形成中的作用提供了机制上的见解，为阿尔茨海默病开辟了新的治疗选择。包含 Aβ 胆固醇结合域的 Aβ22-35 肽诱导神经细胞中 Ca（2+）水平的特异性增加。V24G/K28G 和 N27R/K28R 双突变修饰了胆固醇结合并阻断了通道形成。分子动力学模拟表明胆固醇诱导形成倾斜的 α-螺旋肽拓扑结构，促进环形八聚体通道的形成，如图所示（两个相邻的肽之间的氢键用绿色表示）。总的来说，这些数据深入了解了胆固醇在淀粉样通道形成中的作用，并为阿尔茨海默病开辟了新的治疗选择。
