Non-micellar ganglioside GM1 induces an instantaneous conformational change in Aβ leading to the modulation of the peptide amyloid-fibril pathway.

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 Aβ 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 Aβ intermediate species leading to a possible formation of GM1-modified Aβ fibril. Statistically, no significant difference in toxicity to RA-differentiated SH-SY5Y cells was observed between Aβ fibrils and GM1-tweaked Aβ aggregates. Moreover, GM1-modified Aβ aggregates exhibited prion-like properties in catalyzing the amyloid fibril formation of both major isomers of Aβ, Aβ, and Aβ.