Amyloid-β fibrils assembled on ganglioside-enriched membranes contain both parallel β-sheets and turns

Abstract

Some protein and peptide aggregates, such as those of amyloid-β protein (Aβ), are neurotoxic and have been implicated in several neurodegenerative diseases. Aβ accumulates at nanoclusters enriched in neuronal lipids called gangliosides in the presynaptic neuronal membrane, and the resulting oligomeric and/or fibrous forms accelerate the development of Alzheimer's disease. Although the presence of Aβ deposits at such nanoclusters is known, the mechanism of their assembly and the relationship between Aβ secondary structure and topography are still unclear. Here, we first confirmed by atomic force microscopy that Aβ fibrils can be obtained by incubating seed-free Aβ monomers with a membrane composed of sphingomyelin, cholesterol, and the ganglioside GM1. Using Fourier transform infrared (FTIR) reflection-absorption spectroscopy, we then found that these lipid-associated fibrils contained parallel β-sheets, whereas self-assembled Aβ molecules formed antiparallel β-sheets. We also found that the fibrils obtained at GM1-rich nanoclusters were generated from turn Aβ Our findings indicate that Aβ generally self-assembles into antiparallel β-structures but can also form protofibrils with parallel β-sheets by interacting with ganglioside-bound Aβ. We concluded that by promoting the formation of parallel β-sheets, highly ganglioside-enriched nanoclusters help accelerate the elongation of Aβ fibrils. These results advance our understanding of ganglioside-induced Aβ fibril formation in neuronal membranes and may help inform the development of additional therapies for Alzheimer's disease.

β‐Amyloid aggregation and heterogeneous nucleation

“…In one study, using ganglioside-enriched, planar bilayers, (20:40:40 monolayers of GM1, SM, and cholesterol on POPC-coated mica), AFM showed fibril formation, and FTIR reflection-absorption spectroscopy suggested parallel β-sheet structure. 105 Fibrils formed in the absence of these lipids had FTIR spectra suggestive of antiparallel β-sheet structure, though these results need to be interpreted cautiously, because FTIR has previously suggested antiparallel β-sheet structure when higher resolution and more detailed solid-state NMR ultimately proved parallel β-sheet structure. 109 An important remaining question in these studies is the nature of the interaction between Aβ peptide and gangliosides such as GM 1 .…”

“…There have been only limited studies on the structure of fibrils formed on a ganglioside substratum, but most of these suggest that the fibrils thus formed have the parallel, in‐register β‐sheet structure of most mature amyloid fibrils. In one study, using ganglioside‐enriched, planar bilayers, (20:40:40 monolayers of GM1, SM, and cholesterol on POPC‐coated mica), AFM showed fibril formation, and FTIR reflection–absorption spectroscopy suggested parallel β‐sheet structure . Fibrils formed in the absence of these lipids had FTIR spectra suggestive of antiparallel β‐sheet structure, though these results need to be interpreted cautiously, because FTIR has previously suggested antiparallel β‐sheet structure when higher resolution and more detailed solid‐state NMR ultimately proved parallel β‐sheet structure …”

Modeling neuronopathic storage diseases with patient-derived culture systems

“…A-beta accumulations have also been noted to occur in ganglioside-rich regions of the presynaptic terminal (Yamamoto et al, 2008) (see also figure 1), and can tightly bind to GM1 ganglioside (Yanagisawa et al, 1995). These interactions can induce the seeding of a-beta aggregates with fibrillar morphologies and beta-sheet structures (Matsubara et al, 2018;Yanagisawa, 2007). GM1 ganglioside may play a role in the pathogenesis of Alzheimer's disease through these mechanisms, and some studies have shown that a-beta accumulates in GM1 postmortem brain (Keilani et al, 2012).…”

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

“…Oligomeric Aβ peptides aggregate around lipid rafts embedded in neuronal cell membranes. Recently, it has been shown that GM1 interacts with Aβ peptides, which induces self-assembly of β-sheets leading to polymerization, formation of fibrils and ultimately neurodegeneration [146]. This may be problematic as polymerization of Aβ fibrils may disrupt extracellular trafficking and communication between cells.…”