Sugar distributions on gangliosides guide the formation and stability of amyloid-β oligomers

• Published in: Biophysical chemistry 2023-09, Vol.300, p.107073-107073, Article 107073
• Main Authors: Saha, Jhinuk, Ford, Brea J., Wang, Xianjun, Boyd, Sydney, Morgan, Sarah E., Rangachari, Vijayaraghavan
• Format: Article
• Language: English
• Subjects: Aggregation; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyloid-β; Gangliosides; Gangliosides - chemistry; Gangliosides - metabolism; Humans; Oligomers; Peptide Fragments - chemistry; Protein Binding; Sugars
• ISSN: 0301-4622; 1873-4200; 1873-4200
• DOI: 10.1016/j.bpc.2023.107073

Aggregation of Aβ peptides is a key contributor to the etiology of Alzheimer's disease. Being intrinsically disordered, monomeric Aβ is susceptible to conformational excursions, especially in the presence of important interacting partners such as membrane lipids, to adopt specific aggregation pathways. Furthermore, components such as gangliosides in membranes and lipid rafts are known to play important roles in the adoption of pathways and the generation of discrete neurotoxic oligomers. Yet, what roles do carbohydrates on gangliosides play in this process remains unknown. Here, using GM1, GM3, and GD3 ganglioside micelles as models, we show that the sugar distributions and cationic amino acids within Aβ N-terminal region modulate oligomerization of Aβ temporally, and dictate the stability and maturation of oligomers. These results demonstrate the selectivity of sugar distributions on the membrane surface toward oligomerization of Aβ and thus implicate cell-selective enrichment of oligomers. [Display omitted] •Gangliosides are important membrane components linked to the etiology of Alzheimer's disease.•Sugar distributions on gangliosides GM1, GM3, and GD3 differentially affect the oligomerization of Aβ42.•Aβ-sugar interactions are affected by the cationic residues in the N-terminal of Aβ.•Sugar distribution on ganglioside confers specificity of interaction for the formation and stability of oligomers.