A Kinetic Map of the Influence of Biomimetic Lipid Membrane Models on Aβ42 Aggregation

The aggregation of the amyloid β peptide (Aβ) is one of the major molecular hallmarks of Alzheimer′s disease. Although Aβ deposits have been mostly observed extracellularly, various studies have reported the presence of also intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of Alzheimer′s disease, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein (APP), from which Aβ is derived by proteolytic cleavage. Since lipid bilayers have been shown to promote the aggregation of Aβ, in this study we measure the effects of the lipid membrane composition on the in vitro aggregation kinetics of the 42-residue form of Aβ (Aβ42). By using small unilamellar vesicles modelling cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the endoplasmic reticulum (ER), and the Golgi apparatus, we show that Aβ42 aggregation is inhibited by the ER and Golgi membranes. These results provide a preliminary map of the possible effects of the membrane composition in different cellular locations on Aβ aggregation, and suggest the presence of an evolutionary optimization of lipid composition to prevent the intracellular aggregation of Aβ. ### Competing Interest Statement The authors have declared no competing interest.