Ganglioside GM1 slows down Aβ(1-42) aggregation by a primary nucleation inhibitory mechanism that is modulated by sphingomyelin and cholesterol
Year: 2025
Type: article
Abstract: The conversion of soluble amyloid-β peptides into fibrils is central in Alzheimer's disease. Lipids modulate amyloid-β 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-β variant Aβ(1-42) by which membrane-associated GM1 sequesters soluble Aβ(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 Aβ(1-42) aggregation. The study thereby highlights a versatile, regulatory role of membranes in the molecular pathology of Alzheimer's disease.
Source: Communications Chemistry
Authors: Nima Sasanian, Vesa Halipi, Mikaela Sjögren, Johannes Bengtsson, David Bernson, Elin K. Esbjörner
Institution: Chalmers University of Technology
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,690
OpenAlex ID: W4417321518