title: Density of GM1 in nanoclusters is a critical factor in the formation of a spherical assembly of amyloid β-protein on synaptic plasma membranes.
abstract: The deposition of amyloid β-protein (Aβ) is a pathological hallmark of Alzheimer's disease (AD). We previously found that the ganglioside-enriched microdomains (ganglioside clusters) in presynaptic neuronal membranes play a key role in the initiation of the Aβ assembly process. However, not all ganglioside clusters accelerate Aβ assembly. In the present study, we directly observed a spherical Aβ in an atomic force microscopic study on the morphology of a reconstituted lipid bilayer composed of lipids that were extracted from a detergent-resistant membrane microdomain (DRM) fraction of synaptosomes prepared from aged mouse brain. The Aβ assembly was generated on a distinctive GM1 domain, which was characterized as the Aβ-sensitive ganglioside nanocluster (ASIGN). By using an artificial GM1 cluster-binding peptide, ASIGN was found to have a high density of GM1; therefore, there would be a critical density of GM1 in nanoclusters to induce Aβ binding and assembly. These results suggest that ganglioside-bound Aβ (GAβ), which acts as an endogenous seed for Aβ fibril formation in AD brains, is generated on ASIGN on synaptosomal membranes.
authors.affiliation: Department of Biosciences and Informatics, Keio University, Kouhoku-ku, Yokohama, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Matsubara
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Iijima
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Sato
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D005677:G(M1) Ganglioside / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D051379:Mice; D018625:Microscopy, Atomic Force / Q000379:methods; D013570:Synaptic Membranes / Q000737:chemistry*; D013574:Synaptosomes / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D005677:G(M1) Ganglioside