GM1 inhibits amyloid beta-protein-induced cytokine release

The ganglioside GM1 is known to play a pivotal role in neuronal survival an d/or regeneration. Recently it has been shown that GM1 binds tightly with m embrane-bound amyloid beta protein (A beta) and prevents its conversion fro m a helical to a beta-sheet structure. To examine the potential physiologic al consequences of this binding, we studied the effect of GM1 on A beta-sti mulated release of proinflammatory cytokines, such as interleukin (IL)-1 be ta, IL-6 and TNF-alpha, using the human monocytic cell line, THP-I, as a mo del system. Treatment of THP-1 cells with A beta 1-40 or A beta 25-35 resul ted in an increased cytokine release from these cells. However, treatment o f A beta-activated THP-1 cells with GM1 and several other complex gangliosi des, but not hematosides and neutral glycosphingolipids such as asialo-GM1 (GA1), lactosylceramide, and globoside, significantly decreased the cytokin e release. In contrast, this effect was not observed for lipopolysaccharide (LPS)activated and thrombin-activated THP-1 cells, indicating that the gan glioside effect is specific for A beta-induced cytokine release. A direct i nteraction between GM1 and A beta was demonstrated using the surface plasmo n resonance technique. We found that GM1 ganglioside exhibited higher affin ity far 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 inhibit ory effect of GM1 on A beta-induced cytokine release may reflect pre-existi ng abnormalities in membrane transport at the stage of amyloid formation an d that GM1 may induce conformational changes in A beta, resulting in dimini shed fibrillogenesis and prevention of the inflammatory response of neurona l cells in Alzheimer's disease.