The Double-Layered Structure of Amyloid-beta Assemblage on GM1-Containing Membranes Catalytically Promotes Fibrillization

Alzheimer's 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 offer structural clues for designing drugs targeting catalytically active A beta conformational species for the development of anti-AD therapeutics.