Ganglioside G_M1-Mediated Amyloid-beta Fibrillogenesis and Membrane Disruption

Abstract

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.

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

“…During incubation with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine vesicles containing physiological levels of GM1, the association of Ab with vesicles seeds the formation of Ab fibrils. Thus, favorable interactions between Ab and GM1 in the cell membrane provide a mechanism for Ab fibrillogenesis in vivo, and Ab-induced disruption of the cell membrane may provide a pathway by which Ab exerts toxicity (61).…”

Small Amphipathic Molecules Modulate Secondary Structure and Amyloid Fibril-forming Kinetics of Alzheimer Disease Peptide Aβ1–42

“…Indeed, several studies have visualized extensive A␤ association with cell and synthetic membranes (9,10). These surfaces have been shown either to increase the degree of amyloid fibril formation or to inhibit the process, based on the charge, curvature, and composition of the lipid surface (11)(12)(13)(14). Given that the composition of the surface has a significant impact on the self-association and aggregation of A␤, it is highly likely that individual lipid molecules can also impact on these processes.…”

The interaction of amyloid Aβ(1–40) with lipid bilayers and ganglioside as studied by 31P solid-state NMR

“…Indeed, a number of studies have shown that Aβ is able to perturb lipid bilayers (Arispe et al, 1993). Interest in studies of the interaction between Aβ and constituents of brain membranes has been further stimulated by the identification of an Aβ-GM1 ganglioside-bound form in AD brain (Chi et al, 2007; Kakio et al, 2002;Yanagisawa et al, 1995). …”