Ganglioside-Enriched Phospholipid Vesicles Induce Cooperative Aβ Oligomerization and Membrane Disruption

Abstract

A major hallmark of Alzheimer's disease (AD) is the accumulation of extracellular aggregates of amyloid-β (Aβ). Structural polymorphism observed among Aβ fibrils in AD brains seem to correlate with the clinical subtypes suggesting a link between fibril polymorphism and pathology. Since fibrils emerge from a templated growth of low-molecular-weight oligomers, understanding the factors affecting oligomer generation is important. Membrane lipids are key factors to influence early stages of Aβ aggregation and oligomer generation, which cause membrane disruption. We have previously demonstrated that conformationally discrete Aβ oligomers can be generated by modulating the charge, composition, and chain length of lipids and surfactants. Here, we extend our studies into liposomal models by investigating Aβ oligomerization on large unilamellar vesicles (LUVs) of total brain extracts (TBE), reconstituted lipid rafts (LRs), or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Varying the vesicle composition by specifically increasing the amount of GM1 gangliosides as a constituent, we found that only GM1-enriched liposomes induce the formation of toxic, low-molecular-weight oligomers. Furthermore, we found that the aggregation on liposome surface and membrane disruption are highly cooperative and sensitive to membrane surface characteristics. Numerical simulations confirm such a cooperativity and reveal that GM1-enriched liposomes form twice as many pores as those formed in the absence GM1. Overall, this study uncovers mechanisms of cooperativity between oligomerization and membrane disruption under controlled lipid compositional bias, and refocuses the significance of the early stages of Aβ aggregation in polymorphism, propagation, and toxicity in AD.

The Influence of Lipid Electric Charge on the Binding of Aβ(1–42) Amyloid Peptide to Bilayers in the Liquid-Ordered State

“…Ahyayauch et al [ 18 ] showed that GM1 ganglioside was a major enhancer of Aβ binding to lipid bilayers in the L o state. In fact, gangliosides have repeatedly been described as promoting oligomer and fibril formation, in which their net negative charge is presumably involved [ 8 , 9 , 10 , 11 , 42 ]. The ganglioside effect may be non-linear with the dose.…”

“…Most of the peptide was found either in the L d phase or at the boundary between ordered and disordered phases, in agreement with the data from Alvarez et al [ 6 ]. Several studies pointed out the facilitating role of GM1 ganglioside in Aβ oligomerization [ 8 , 9 , 10 , 11 ]. Cholesterol was also found to positively modulate Aβ oligomerization [ 7 , 12 ].…”

Ganglioside GM1 produces stable, short, and cytotoxic Aβ40 protofibrils

“…7,8 Several studies have demonstrated that ganglioside micelle, or clusters in the membrane, catalyze toxic Ab species' formation. [9][10][11][12][13][14][15][16][17] Additionally, free lipids have been shown to modulate the aggregation kinetics of Ab peptides. [18][19][20][21] This in vitro study is focused on unraveling the molecular processes underlying the early conformational changes of Ab induced by the interaction with GM1, which have been linked to early AD onset.…”

Ganglioside GM1 produces stable, short, and cytotoxic Aβ40protofibrils

“…7,8 Several studies have demonstrated that ganglioside clusters in the membrane catalyze the formation of toxic Aβ species. [9][10][11][12][13][14][15][16][17] Additionally, free lipids have been shown to modulate the aggregation kinetics of Aβ peptides. [18][19][20][21] This in vitro study is focused on unraveling the molecular processes underlying the early conformational changes of Aβ induced by the interaction with GM1, which have been linked to early AD onset.…”