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bioRxiv · 10.1101/2022.06.26.497640

The double-layered structure of amyloid-β assemblage on GM1-containing membranes catalytically promotes fibrillization

Yagi-Utsumi, M.·Itoh, S. G.·Okumura, H.·Yanagisawa, K.·Kato, K.·Nishimura, K.
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Abstract

Alzheimers disease (AD) is associated with progressive accumulation of amyloid-{beta} (A{beta}) cross-{beta} fibrils in the brain. A{beta} species tightly associated with GM1 ganglioside, a glycosphingolipid abundant in neuronal membranes, promote amyloid fibril formation; therefore, they could be attractive clinical targets. However, the active conformational state of A{beta} in GM1-containing lipid membranes is still unknown. The present solid-state nuclear magnetic resonance study revealed a nonfibrillar A{beta} assemblage characterized by a double-layered antiparallel {beta}-structure specifically formed on GM1 ganglioside clusters. Our data show that this unique assemblage was not transformed into fibrils on GM1-containing membranes, but could promote conversion of monomeric A{beta} into fibrils, suggesting that a solvent-exposed hydrophobic layer provides a catalytic surface evoking A{beta} fibril formation. Our findings will offer structural clues for designing drugs targeting catalytically active A{beta} conformational species for the development of anti-AD therapeutics.

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Yagi-Utsumi, M., Itoh, S. G., Okumura, H., Yanagisawa, K., Kato, K., Nishimura, K.. 2022-06-29. The double-layered structure of amyloid-β assemblage on GM1-containing membranes catalytically promotes fibrillization. https://doi.org/10.1101/2022.06.26.497640

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