TY - JOUR
T1 - GM1 inhibits amyloid β-protein-induced cytokine release
AU - Ariga, Toshio
AU - Yu, Robert K.
N1 - Funding Information:
We are grateful to Dr. Tadashi Miyatake, Showa Pharmaceutical College, Machida, Japan, and Dr. H. T. Wright, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, for helpful discussions. This work was supported in part by a USPHS grant NS11853-24 to RKY.
PY - 1999
Y1 - 1999
N2 - 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 β protein (Aβ) and prevents its conversion from a helical to a β-sheet structure. To examine the potential physiological consequences of this binding, we studied the effect of GM1 on Aβ-stimulated release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6 and TNF-α, using the human monocytic cell line, THP-1, as a model system. Treatment of THP-1 cells with Aβ 1-40 or Aβ 2535 resulted in an increased cytokine release from these cells. However, treatment of Aβ-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 Aβ-induced cytokine release. A direct interaction between GM1 and Aβ was demonstrated using the surface plasmon resonance technique. We found that GM1 ganglioside exhibited higher affinity for Aβ 1-40 than GA1, suggesting that the sialic acid moiety of GM1 is necessary for its interaction with Aβ. We conclude that the inhibitory effect of GM1 on Aβ- 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 Aβ, resulting in diminished fibrillogenesis and prevention of the inflammatory response of neuronal cells in Alzheimer's disease.
AB - 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 β protein (Aβ) and prevents its conversion from a helical to a β-sheet structure. To examine the potential physiological consequences of this binding, we studied the effect of GM1 on Aβ-stimulated release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6 and TNF-α, using the human monocytic cell line, THP-1, as a model system. Treatment of THP-1 cells with Aβ 1-40 or Aβ 2535 resulted in an increased cytokine release from these cells. However, treatment of Aβ-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 Aβ-induced cytokine release. A direct interaction between GM1 and Aβ was demonstrated using the surface plasmon resonance technique. We found that GM1 ganglioside exhibited higher affinity for Aβ 1-40 than GA1, suggesting that the sialic acid moiety of GM1 is necessary for its interaction with Aβ. We conclude that the inhibitory effect of GM1 on Aβ- 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 Aβ, resulting in diminished fibrillogenesis and prevention of the inflammatory response of neuronal cells in Alzheimer's disease.
KW - Alzheimer's disease
KW - Amyloid β-protein
KW - Cytokines
KW - GM1 ganglioside
KW - Interleukin-1 β, interleukin-6
KW - Tumor necrosis factor- α
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U2 - 10.1023/A:1022557920150
DO - 10.1023/A:1022557920150
M3 - Article
C2 - 9972868
AN - SCOPUS:0032903798
SN - 0364-3190
VL - 24
SP - 219
EP - 226
JO - Neurochemical Research
JF - Neurochemical Research
IS - 2
ER -