Interactions of Amyloid #beta#-Protein wiht Varous Gangliosides in Raft-Like Membranes: Importance of GM1 Ganglioside-Bound Form as an Endogenous Seed for Alzheimer Amyloid

摘要

GM1 ganglioside-bound amyloid #beta#-protein (GM1-A#beta#), found in brains exhibiting early pathological changes of alzheimer's disease (AD) plaques, has been suggested to accelerate amyloid fibril formation by acting as a seed. We have previously found using dye-labeled a #beta# that A #beta# recognizes a GM1 cluster, the formation of which is facilitated by cholesterol [Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y., and Matsuzaki, K. (2001) J. Biol. Chem. 276, 24985-24990]. In this study, we investigated the ganglioside species-specificity in its potency to induce a conformational change of A#beta#, by which gangliosid-bound A#beta# acts as a seed for A#beta# fibril genesis, using a major ganglioside occurring in brains (GM1, GD1a, GD1b, and GT1b) in raft-like membranes composed of cholesterol and shpingomyelin. A#beta# recognized gangioside clusters, the density of which increased with the number of silica acid residues. Interestingly, however, mixing of gangliosides inhibited cluster formation. In contrast, the affinities of the protein for the clusters were similar irrespective of lipid composition and of the order of 10~6 M~(-1) at 37 deg C. A#beta# underwent a conformational transition from an #alpha#-helix-rich structure to a #beta#-sheet-rich structure with the increase in protein density on the membrane. Ganglioside-bound A#beta# proteins exhibited seeding abilities for amyloid formation. GM1 -A#beta# exhibited the strongest seeding potential, especially under #beta#-sheet-forming conditions. This study suggested that lipid composition including ganglisosides and cholesterol strictly controls amyloid formation.