High speed atomic force microscopy to investigate the interactions between toxic Aβ_1-42 peptides and model membranes in real time: impact of the membrane composition

Abstract

For investigating Alzheimer's disease mechanisms, high-speed atomic force microscopy is a proper tool to monitor the interactions between toxic peptides and lipid model membranes.

High Speed AFM and NanoInfrared Spectroscopy Investigation of Aβ1–42 Peptide Variants and Their Interaction With POPC/SM/Chol/GM1 Model Membranes

“…The Aβ 1-42 WT peptides, as well as Aβ 1-42 L34T present similar initial morphologies with small globular species below 10 nm in diameter on the mica substrates. In the case of the oligomer Aβ 1-42 oG37C, larger globular aggregates are preferentially observed with sizes ranging from 20 to 50 nm in diameter, with occasional small globular objects (5-10 nm) still present, corresponding to previously observed isolated oligomers (Bonhommeau et al, 2017;Ewald et al, 2019).…”

“…This oG37C oligomer is stable in solution as a 14-mer (Bobo et al, 2017), does not form fibers and shows the highest toxicity in yeast, which makes it the perfect model homogeneous oligomer to better understand the oligomer/membrane interaction with model membranes of controlled lipid compositions. Model membranes composed of Sphingomyelin (SM), 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC), Cholesterol (Chol), and ganglioside GM1 have been used as they have previously been shown to have a strong interaction with the Aβ peptides (Ewald et al, 2019) leading to their disruption after addition of toxic peptides. In this paper, using NanoIR and HS-AFM, we try to answer the question whether the behavior of the mutant oligomer oG37C reflects the one of WT Aβ 1-42 peptides, and whether it is possible to obtain a correlation between the toxicity of the peptides, their morphologies and structures, and their interactions with SM/PC/Chol/GM1 membranes.…”

The Binding of Aβ42 Peptide Monomers to Sphingomyelin/Cholesterol/Ganglioside Bilayers Assayed by Density Gradient Ultracentrifugation

“…Different ganglioside concentrations may either accelerate or inhibit amyloid formation by the pancreatic islet amyloid polypeptide [36] or by Aβ42 (Ahyayauch, H., unpublished results), and this may in turn have pathological consequences [37]. There are also contradictory data on the role of Chol in Aβ42-binding to bilayers, from those that suggest a positive role in Aβ42 binding and aggregation [19,38] to those who propose a negative influence [39] or a dual effect depending on Chol concentration [40]. In general, Chol appears to have a negative effect on Aβ binding and aggregation particularly in the absence of sphingolipids [41,42].…”

“…This provides the most direct evidence to date of the long-proposed positive role of gangliosides in facilitating Aβ binding to lipid bilayers. The role of gangliosides as facilitators was shown, in less direct ways, by different authors [15,[17][18][19][20][21]. Amaro et al [17] had indicated that, under certain conditions, gangliosides inhibited Aβ oligomerization induced by SM.…”

“…Numerous studies have explored model membranes composed of SM, Chol and gangliosides. Selected examples include those based on molecular dynamics [16][17][18], atomic force microscopy (AFM) [19,20], infrared spectroscopy [21], and other biophysical techniques [22,23]. To our knowledge Aβ42 binding to bilayers after separation of the free and lipid-bound forms of the peptide by density gradient centrifugation have rarely been performed.…”