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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects cognition and memory. Recent advances have helped identify many clinical sub‐types in AD. Mounting evidence point toward structural polymorphism among fibrillar aggregates of amyloid‐β (Aβ) to being responsible for the phenotypes and clinical manifestations. In the emerging paradigm of polymorphism and prion‐like propagation of aggregates in AD, the role of low molecular weight soluble oligomers, which are long known to be the primary toxic agents, in effecting phenotypes remains inconspicuous. In this study, we present the characterization of three soluble oligomers of Aβ42, namely 14LPOs, 16LPOs, and GM1Os with discreet biophysical and biochemical properties generated using lysophosphatidyl glycerols and GM1 gangliosides. The results indicate that the oligomers share some biophysical similarities but display distinctive differences with GM1Os. Unlike the other two, GM1Os were observed to be complexed with the lipid upon isolation. It also differs mainly in detection by conformation‐sensitive dyes and conformation‐specific antibodies, temperature and enzymatic stability, and in the ability to propagate morphologically‐distinct fibrils. GM1Os also show distinguishable biochemical behavior with pronounced neuronal toxicity. Furthermore, all the oligomers induce cerebral amyloid angiopathy (CAA) and plaque burden in transgenic AD mice, which seems to be a consistent feature among all lipid‐derived oligomers, but 16LPOs and GM1Os displayed significantly higher effect than the others. These results establish a correlation between molecular features of Aβ42 oligomers and their distinguishable effects in transgenic AD mice attuned by lipid characteristics, and therefore help bridge the knowledge gap in understanding how oligomer conformers could elicit AD phenotypes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]