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Alzheimer's disease is a progressive degenerative condition that mainly affects cognition and memory. Recently, distinct clinical and neuropathological phenotypes have been identified in AD. Studies revealed that structural variation in Aβ fibrillar aggregates correlates with distinct disease phenotypes. Moreover, environmental surroundings, including other biomolecules such as proteins and lipids, have been shown to interact and modulate Aβ aggregation. Model membranes containing ganglioside (GM1) clusters are specifically known to promote Aβ fibrillogenesis. This study unravels the modulatory effect of non-micellar GM1, a glycosphingolipid frequently released from the damaged neuronal membranes, on Aβ42 amyloid fibril formation. Using far-UV circular dichroism experiments, we observed a change in the peptide secondary structure from random-coil to β-turn structures with subsequent generation of predominantly β-sheet-rich species upon interaction with GM1. Thioflavin-T (ThT) fluorescence assays further indicated that GM1 likely interacts with an amyloidogenic Aβ42 intermediate species leading to a possible formation of GM1-modified Aβ42 fibril. Statistically, no significant difference in toxicity to RA-differentiated SH-SY5Y cells was observed between Aβ42 fibrils and GM1-tweaked Aβ42 aggregates. Moreover, GM1-modified Aβ42 aggregates exhibited prion-like properties in catalyzing the amyloid fibril formation of both major isomers of Aβ, Aβ40, and Aβ42. Copyright © 2023. Published by Elsevier B.V.
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