Complexity in lipid membrane composition induces resilience to Aβ42 aggregation.

The molecular origins of Alzheimer's disease are associated with the aggregation of the amyloid-β peptide (Aβ). This process is controlled by a com-plex cellular homeostasis system, which involves a variety of components, including proteins, metabo-lites 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-residues form of Aβ (Aβ42), ranging from enhancement to inhibi-tion. We then show that these effects tend to aver-age out in mixtures of these lipids, as such mixtures buffer extreme aggregation behaviors as the num-ber of components increases. These results indicate that a degree of quality control on protein aggrega-tion can be achieved through a mechanism by which an increase in the molecular complexity of lipid membranes balances opposite effects and cre-ates resilience to aggregation.