LAUSR

AbstractThe assembly of amyloid ß protein (Aß) on ganglioside-enriched microdomains in presynaptic neuronal membranes is involved in the onset of Alzheimer’s disease. We previously found that a highly enriched ganglioside domain generated in a reconstituted lipid bilayer composed of synaptosomal lipids functioned as an Aß-sensitive ganglioside nanocluster (ASIGN) that may induce a spherical Aß assembly. In the present study, the major lipid components of a detergent-resistant membrane microdomain (DRM) fraction of synaptosomes prepared from an aged mouse brain were identified, and we demonstrate that the proportion of Aß-insensitive gangliosides such as GM3 directly affects the Aß assembly in synaptosomal membranes. Liquid chromatography coupled to mass spectrometry analyses indicated that ganglio a-series gangliosides (GM1, GM2, GM3, and GD1a) were abundant in DRM fractions. In addition, the GM3/GM1 ratio and the cholesterol content in the synaptosomal fraction differed from those in the non-synaptosomal fraction, in which GM1 and GM3 are sensitive and insensitive gangliosides, respectively. The highly enriched ganglioside nanocluster was identified by the surface topography of ternary mixed lipid bilayers composed of gangliosides, sphingomyelin, and cholesterol. Our results indicate that the composition of gangliosides is responsible for the characteristics of the nanocluster generated in the presynaptic neuronal membranes.Amyloid ß-protein (Aß) is converted to toxic forms through interactions with the ganglioside in neuronal membranes. The highly ganglioside-enriched microdomain (ganglioside cluster) in neuronal membranes plays a key role in Aß assembly. In the present study, lipid components of synaptosome extracted from mouse aged brain was determined by LC-MS spectroscopy. We demonstrated that ganglioside ratio (GM3 to GM1) and cholesterol content are an important factor for inducing Aß assembly. These results provides important insight into the mechanism of polypeptide assembly on the neuronal membrane in Alzheimer’s disease patients.