The molecular origins of Alzheimer's disease are associated with the aggregation of the amyloid-β peptide (Aβ). This process is controlled by a complex cellular homeostasis system, which involves a variety of components, including proteins, metabolites, and lipids. It has been shown in particular that certain components of lipid membranes can speed up Aβ aggregation. This observation prompts the question of whether there are protective cellular mechanisms to counterbalance this effect. Here, to address this issue, we investigate the role of the composition of lipid membranes in modulating the aggregation process of Aβ. By adopting a chemical kinetics approach, we first identify a panel of lipids that affect the aggregation of the 42-residue form of Aβ (Aβ42), ranging from enhancement to inhibition. We then show that these effects tend to average out in mixtures of these lipids, as such mixtures buffer extreme aggregation behaviors as the number of components increases. These results indicate that a degree of quality control on protein aggregation can be achieved through a mechanism by which an increase in the molecular complexity of lipid membranes balances opposite effects and creates resilience to aggregation.

中文翻译：

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脂质膜成分的复杂性诱导对Aβ42聚集的抗性。

阿尔茨海默氏病的分子起源与淀粉样β肽（Aβ）的聚集有关。该过程由复杂的细胞动态平衡系统控制，该系统涉及多种成分，包括蛋白质，代谢产物和脂质。特别显示出脂质膜的某些组分可以加速Aβ聚集。这一发现提示了是否存在保护性细胞机制来抵消这种作用的问题。在这里，为了解决这个问题，我们研究了脂质膜成分在调节Aβ聚集过程中的作用。通过采用化学动力学方法，我们首先确定了一组脂质，这些脂质影响从增强到抑制的42个残基形式的Aβ（Aβ42）的聚集。然后，我们表明这些效应在这些脂质的混合物中趋于平均，因为随着组分数量的增加，此类混合物会缓冲极端的聚集行为。这些结果表明，可以通过一种机制来实现对蛋白质聚集的质量控制，通过该机制脂质膜分子复杂性的增加平衡了相反的作用并产生了对聚集的弹性。