GM1 inhibits amyloid beta-protein-induced cytokine release.
The ganglioside GM1 is known to play a pivotal role in neuronal survival and/or regeneration. Recently it has been shown that GM1 binds tightly with membrane-bound amyloid beta protein (A beta) and prevents its conversion from a helical to a beta-sheet structure. To examine the potential physiological consequences of this binding, we studied the effect of GM1 on A beta-stimulated release of proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and TNF-alpha, using the human monocytic cell line, THP-1, as a model system. Treatment of THP-1 cells with A beta 1-40 or A beta 25-35 resulted in an increased cytokine release from these cells. However, treatment of A beta-activated THP-1 cells with GM1 and several other complex gangliosides, but not hematosides and neutral glycosphingolipids such as asialo-GM1 (GA1), lactosylceramide, and globoside, significantly decreased the cytokine release. In contrast, this effect was not observed for lipopolysaccharide (LPS)-activated and thrombin-activated THP-1 cells, indicating that the ganglioside effect is specific for A beta-induced cytokine release. A direct interaction between GM1 and A beta was demonstrated using the surface plasmon resonance technique. We found that GM1 ganglioside exhibited higher affinity for A beta 1-40 than GA1, suggesting that the sialic acid moiety of GM1 is necessary for its interaction with A beta. We conclude that the inhibitory effect of GM1 on A beta-induced cytokine release may reflect pre-existing abnormalities in membrane transport at the stage of amyloid formation and that GM1 may induce conformational changes in A beta, resulting in diminished fibrillogenesis and prevention of the inflammatory response of neuronal cells in Alzheimer's disease.
Ariga
T
T
Eisai Co., Ltd., Tokyo, Japan.
Yu
R K
RK
D016229:Amyloid beta-Peptides / Q000502:physiology*; D002460:Cell Line; D005677:G(M1) Ganglioside / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*