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Ganglioside GM1 slows down Abeta(1-42) aggregation by a primary nucleation inhibitory mechanism that is modulated by sphingomyelin and cholesterol #MMPMID41390894
Sasanian N; Halipi V; Sjogren M; Bengtsson J; Bernson D; Esbjorner EK
Commun Chem 2025[Dec]; ? (?): ? PMID41390894show ga
The conversion of soluble amyloid-beta peptides into fibrils is central in Alzheimer's disease. Lipids modulate amyloid-beta aggregation, but whilst the mechanistic effect of individual lipid species is increasingly addressed, principles explaining their combinatorial contributions in biologically heterogenous membranes remain to be established. We used kinetic analyses to establish an inhibitory mechanism of GM1 gangliosides on the aggregation of amyloid-beta variant Abeta(1-42) by which membrane-associated GM1 sequesters soluble Abeta(1-42) and retards primary nucleation. The kinetic inhibition increased in presence of the raft-enabling lipids cholesterol and sphingomyelin, although these lipids, intrinsically, catalysed primary and secondary nucleation respectively. These results decipher important trade-offs between the specific chemical properties of lipids and their general contributions to the physical state of membranes, show principles of competition, and identify low fluidity domains as key regulators of membrane-mediated Abeta(1-42) aggregation. The study thereby highlights a versatile, regulatory role of membranes in the molecular pathology of Alzheimer's disease.
Commun+Chem 2025 ; ? (?): ?
