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bioRxiv · 10.1101/2023.05.12.540574

Non-micellar ganglioside GM1 induces an instantaneous conformational change in Aβ42 leading to the modulation of the peptide amyloid-fibril pathway

Kumar, M.·Ivanova, M. I.·Ramamoorthy, A.
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Abstract

Alzheimers 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 A{beta} 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 A{beta} aggregation. Model membranes containing ganglioside (GM1) clusters are specifically known to promote A{beta} fibrillogenesis. This study unravels the modulatory effect of non-micellar GM1, a glycosphingolipid frequently released from the damaged neuronal membranes, on A{beta}42amyloid fibril formation. Using far-UV circular dichroism experiments, we observed a spontaneous change in the peptide secondary structure from random-coil to {beta}-turn with subsequent generation of predominantly {beta}-sheet-rich species upon interaction with GM1. Thioflavin-T (ThT) fluorescence assays further indicated that GM1 interacts with the amyloidogenic A{beta}42 primary nucleus leading to a possible formation of GM1-modified A{beta}42 fibril. Statistically, no significant difference in toxicity to RA-differentiated SH-SY5Y cells was observed between A{beta}42 fibrils and GM1-tweaked A{beta}42 aggregates. Moreover, GM1-modified A{beta}42 aggregates exhibited prion-like properties in catalyzing the amyloid fibril formation of both major isomers of A{beta}, A{beta}40, and A{beta}42.

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Kumar, M., Ivanova, M. I., Ramamoorthy, A.. 2023-05-14. Non-micellar ganglioside GM1 induces an instantaneous conformational change in Aβ42 leading to the modulation of the peptide amyloid-fibril pathway. https://doi.org/10.1101/2023.05.12.540574

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