Ganglioside G_(MI)-Mediated Amyloid-beta Fibrillogenesis and Membrane Disruption

摘要

There is increasing evidence that a class of cell membrane glycolipids,gangliosides,can mediate the fibrillogenesis and toxicity of Alzheimer's disease amyloid-beta peptide (A beta).Using lipid monolayers and vesicles as model membranes,we measured the insertion of A beta into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-ganglioside G_(M1) monolayers to probe A beta-G_(M1) interactions,imaged the effects of A beta insertion on monolayer morphology,and measured the rate of A beta fibril formation when incubated with l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)-G_(M1) vesicles.Furthermore,the location of A beta association in the monolayer was assessed by dual-probe fluorescence experiments.A beta exhibited direct and favorable interactions with G_(M1) as A beta insertion monotonically increased with G_(M1) concentration,despite increases in monolayer rigidity at low G_(M1) levels.At low G_(M1) concentrations,A beta preferentially inserted into the disordered,liquid expanded phase.At higher GM1 concentrations,A beta inserted more uniformly into the monolayer,resulting in no detectable preferences for either the disordered or condensed phase.A beta insertion led to the disruption of membrane morphology,specifically to the expansion of the disordered phase at low G_(M1) concentrations and significant disruption of the condensed domains at higher G_(M1) concentrations.During incubation with POPC vesicles containing physiological levels of G_(M1),the association of A beta with vesicles seeded the formation of A beta fibrils.In conclusion,favorable interactions between A beta and G_(M1) in the cell membrane may provide a mechanism for A beta fibrillogenesis in vivo,and A beta-induced disruption of the cell membrane may provide a pathway by which A beta exerts toxicity.