Ganglioside G(M1)-mediated amyloid-beta fibrillogenesis and membrane disruption.
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 (Abeta). Using lipid monolayers and vesicles as model membranes, we measured the insertion of Abeta into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-ganglioside GM1 monolayers to probe Abeta-GM1 interactions, imaged the effects of Abeta insertion on monolayer morphology, and measured the rate of Abeta fibril formation when incubated with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)-GM1 vesicles. Furthermore, the location of Abeta association in the monolayer was assessed by dual-probe fluorescence experiments. Abeta exhibited direct and favorable interactions with GM1 as Abeta insertion monotonically increased with GM1 concentration, despite increases in monolayer rigidity at low GM1 levels. At low GM1 concentrations, Abeta preferentially inserted into the disordered, liquid expanded phase. At higher GM1 concentrations, Abeta inserted more uniformly into the monolayer, resulting in no detectable preferences for either the disordered or condensed phase. Abeta insertion led to the disruption of membrane morphology, specifically to the expansion of the disordered phase at low GM1 concentrations and significant disruption of the condensed domains at higher GM1 concentrations. During incubation with POPC vesicles containing physiological levels of GM1, the association of Abeta with vesicles seeded the formation of Abeta fibrils. In conclusion, favorable interactions between Abeta and GM1 in the cell membrane may provide a mechanism for Abeta fibrillogenesis in vivo, and Abeta-induced disruption of the cell membrane may provide a pathway by which Abeta exerts toxicity.
Chi
Eva Y
EY
Department of Chemistry, The Institute for Biophysical Dynamics, and the James Franck Institute, University of Chicago, 929 E. 57th Street, Chicago, Illinois 60637, USA.
Frey
Shelli L
SL
Lee
Ka Yee C
KY
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D005677:G(M1) Ganglioside / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D008567:Membranes, Artificial; D008856:Microscopy, Fluorescence; D010713:Phosphatidylcholines / Q000737:chemistry
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D015060:1,2-Dipalmitoylphosphatidylcholine; D005677:G(M1) Ganglioside; C028694:1-palmitoyl-2-oleoylphosphatidylcholine