A Kinetic Map of the Influence of Biomimetic Lipid Model Membranes on Aβ₄₂ Aggregation

Abstract

The aggregation of the amyloid β (Aβ) peptide is one of the molecular hallmarks of Alzheimer’s disease (AD). Although Aβ deposits have mostly been observed extracellularly, various studies have also reported the presence of intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of AD, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein, from which Aβ is derived by proteolytic cleavage. Senile plaques found in AD are largely composed of the 42-residue form of Aβ (Aβ42). Intracellularly, Aβ42 is produced in the endoplasmatic reticulum (ER) and Golgi apparatus. 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 Aβ42. By using large unilamellar vesicles to model cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the ER, and the Golgi apparatus, we show that Aβ42 aggregation is inhibited by the ER and Golgi model 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 the lipid composition to prevent the intracellular aggregation of Aβ.

Microfluidic antibody affinity profiling of alloantibody-HLA interactions in human serum

“…Several different techniques have been successfully applied for the characterisation of molecular interactions in research, such as dynamic light scattering (DLS) (Malm and Corbett, 2019), isothermal titration calorimetry (ITC) (Pierce et al, 1999), microscale thermophoresis (MST) (Asmari et al, 2018), nuclear magnetic resonance (NMR) (Wilkins et al, 1999), surface plasmon resonance (SPR) (Mullett et al, 2000;Visentin et al, 2016Visentin et al, , 2018, and the here presented microfluidic diffusional sizing (MDS) (Arosio et al, 2016;Scheidt et al, 2019Scheidt et al, , 2020Scheidt et al, , 2021Schneider et al, 2021;Linse et al, 2020;Emmenegger et al, 2021;Aprile et al, 2020;Ausserwöger et al, 2022). MDS has previously been applied to measure affinities of interactions of molecular chaperones (Scheidt et al, 2019(Scheidt et al, , 2021Schneider et al, 2021), of therapeutic antibodies (Arosio et al, 2016;Linse et al, 2020;Aprile et al, 2020) and design peptides (Sahtoe et al, 2023) with amyloid structures, as well as the characterisation of protein-DNA interactions (Ausserwöger et al, 2022), protein-membrane interactions (Zhang et al, 2020;Baumann et al, 2023), and of protein mixtures (Scheidt et al, 2020). Nevertheless, only enzyme-linked immunosorbent assays (ELISA) (Engvall, 1980;Engvall et al, 1971;Engvall and Perlmann, 1972;Ueda et al, 1996) and bead-based multiplex assays (Carson and Vignali, 1999;Fulton et al, 1997;Joos et al, Abbreviations...…”

The Alzheimer’s Aβ peptide forms biomolecular condensates that trigger amyloid aggregation

“…Changes in brain lipidome have been linked to the development of AD, giving rise to a great interest in understanding the role of lipid surfaces in Aβ42 aggregation in AD (24). Lipid membranes, depending on their composition, affect Aβ42 fibrillation rates (19,20,23) and there is evidence from kinetic studies that membrane surfaces affect primary aggregation pathways of Aβ42 (19), The molecular mechanisms underpinning this acceleration have, however, largely remained unknown. To address this question, we initially probed Aβ42 aggregate formation on lipid membranes by total internal reflection fluorescence (TIRF) and confocal fluorescence microscopy imaging.…”

Molecular Insights for Alzheimer’s Disease: An Unexplored Storyline on the Nanoscale Impact of Nascent Aβ1–42 toward the Lipid Membrane

“…Several arguments are in favor of the intracellular membrane production and aggregation of Aβ. Also, a very recent in vitro study elegantly demonstrated that in various biomimetic model organelle membranes, Aβ 1–42 aggregation kinetics is influenced by lipid composition, especially in the inner endosomal leaflet comparable to the outer leaflet of the plasma membrane . In addition, numerous studies have described the very high affinity of oligomeric Aβ peptides for membranes and membrane lipids but without describing consensually the types of interactions .…”

“…Also, a very recent in vitro study elegantly demonstrated that in various biomimetic model organelle membranes, Aβ 1−42 aggregation kinetics is influenced by lipid composition, especially in the inner endosomal leaflet comparable to the outer leaflet of the plasma membrane. 17 In addition, numerous studies have described the very high affinity of oligomeric Aβ peptides for membranes and membrane lipids but without describing consensually the types of interactions. 18 In differentiated PC12 cells and N2a cells stably expressing APPswe and PS1, the Aβ 1−42 peptide was also found tightly associated with the lysosomal membrane, while its proportion in the lysosomal lumen is minimal.…”