GM₁ Ganglioside Inhibits β‐Amyloid Oligomerization Induced by Sphingomyelin

Abstract

Abstractβ‐Amyloid (Aβ) oligomers are neurotoxic and implicated in Alzheimer's disease. Neuronal plasma membranes may mediate formation of Aβ oligomers in vivo. Membrane components sphingomyelin and GM1 have been shown to promote aggregation of Aβ; however, these studies were performed under extreme, non‐physiological conditions. We demonstrate that physiological levels of GM1, organized in nanodomains do not seed oligomerization of Aβ40 monomers. We show that sphingomyelin triggers oligomerization of Aβ40 and that GM1 is counteractive thus preventing oligomerization. We propose a molecular explanation that is supported by all‐atom molecular dynamics simulations. The preventive role of GM1 in the oligomerization of Aβ40 suggests that decreasing levels of GM1 in the brain, for example, due to aging, could reduce protection against Aβ oligomerization and contribute to the onset of Alzheimer's disease.

Diffusion of lipids and GPI-anchored proteins in actin-free plasma membrane vesicles measured by STED-FCS

“…Yet, hop or compartmentalized diffusion has so far only been observed in the presence of a strong cortical actin meshwork. This favours the model of transient domain incorporation of GM1 in GPMVs which was suggested for artificial vesicles previously (Lozano et al, 2013;Amaro et al, 2016). Thus, our data indicates that the actin cytoskeleton influences diffusion of the phospholipids and sphingomyelin more significantly than of GM1.…”

Diffusion of lipids and GPI-anchored proteins in actin-free plasma membrane vesicles measured by STED-FCS

“…Such transient domain incorporation of GM1 in artificial vesicles was previously suggested (Lozano et al. , 2013; Amaro et al. , 2016).…”

Amyloid beta: structure, biology and structure-based therapeutic development

“…The newly generated Aβ either is released to the extracellular space or remains associated with the plasma membrane and lipid raft structures. The binding of Aβ to ganglioside GM1 in the lipid rafts strongly favors Aβ aggregation [94] . The binding of ApoE to Aβ taken up by the cells through receptor-mediated endocytosis mediated by LRP (LDL receptor-related protein), and LDLR regulates aggregation but also the cellular uptake of Aβ [95] .…”