Abstract
BackgroundGangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson’s disease and Huntington’s disease. In models of both diseases and other conditions, administration of GM1—one of the most abundant gangliosides in the brain—provides neuroprotection. Most studies have focused on the direct neuroprotective effects of gangliosides on neurons, but their role in other brain cells, in particular microglia, is not known. In this study we investigated the effects of exogenous ganglioside administration and modulation of endogenous ganglioside levels on the response of microglia to inflammatory stimuli, which often contributes to initiation or exacerbation of neurodegeneration.MethodsIn vitro studies were performed using BV2 cells, mouse, rat, and human primary microglia cultures. Modulation of microglial ganglioside levels was achieved by administration of exogenous gangliosides, or by treatment with GENZ-123346 and L–t-PDMP, an inhibitor and an activator of glycolipid biosynthesis, respectively. Response of microglia to inflammatory stimuli (LPS, IL-1β, phagocytosis of latex beads) was measured by analysis of gene expression and/or secretion of pro-inflammatory cytokines. The effects of GM1 administration on microglia activation were also assessed in vivo in C57Bl/6 mice, following intraperitoneal injection of LPS.ResultsGM1 decreased inflammatory microglia responses in vitro and in vivo, even when administered after microglia activation. These anti-inflammatory effects depended on the presence of the sialic acid residue in the GM1 glycan headgroup and the presence of a lipid tail. Other gangliosides shared similar anti-inflammatory effects in in vitro models, including GD3, GD1a, GD1b, and GT1b. Conversely, GM3 and GQ1b displayed pro-inflammatory activity. The anti-inflammatory effects of GM1 and other gangliosides were partially reproduced by increasing endogenous ganglioside levels with L–t-PDMP, whereas inhibition of glycolipid biosynthesis exacerbated microglial activation in response to LPS stimulation.ConclusionsOur data suggest that gangliosides are important modulators of microglia inflammatory responses and reveal that administration of GM1 and other complex gangliosides exerts anti-inflammatory effects on microglia that could be exploited therapeutically.
Highlights
Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation
BV2 cells were pre-incubated with GM1 (50 μM) for 1 h and stimulated with LPS (E. coli serotype O55:B5, 100 ng/ml) to activate the Toll-like receptor 4 (TLR-4), a major pattern recognition receptor that is activated by endogenous dangerassociated molecular patterns released in stress and neurodegenerative conditions [48,49,50]
We confirmed these results in primary cultures of mouse and rat microglia, where the administration of GM1 2 h prior to a challenge with LPS blocked the transcription of NFkB target genes, including IL-1β, Tumor necrosis factor (TNF), and Nuclear factor NF-kappa-B (NFκB) inhibitor alpha (IκBα) (Additional file 1: Fig. S1C), and the release of pro-inflammatory cytokines IL-6, IL-1β, and Nitric oxide (NO) in the culture medium (Fig. 1B)
Summary
Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson’s disease and Huntington’s disease. In models of both diseases and other conditions, administration of GM1—one of the most abundant gangliosides in the brain—provides neuroprotection. Inherent to microglia function in the CNS is their involvement in essentially all types of neurological and neurodegenerative conditions [8] In many of these conditions, including Alzheimer’s disease (AD) [9], Huntington’s disease (HD) [10, 11], and Parkinson’s disease (PD) [12, 13], among others, a maladaptive increase in microglia inflammatory responses contributes to disease onset and/or progression [14,15,16]. Therapeutic administration of one of the most abundant brain gangliosides, GM1, provides neuroprotection in models of neuronal injury and neurodegeneration [33,34,35,36,37] and in genetic models of HD [38, 39]
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