Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions

Abstract

ABSTRACTGangliosides are sialic acid-containing glycosphingolipids highly enriched in the brain. Located mainly at the plasma membrane, gangliosides play important roles in signaling and cell-to-cell communication. Lack of gangliosides causes severe early onset neurodegenerative disorders, while more subtle deficits have been reported in Parkinson’s disease and in Huntington’s disease, two misfolded protein diseases with a neuroinflammatory component. On the other hand, administration of ganglioside GM1 provides neuroprotection in both diseases and in several other models of neuronal insult. While most studies have focused on the role of endogenous gangliosides and the effects of exogenously administered GM1 in neurons, their contribution to microglia functions that are affected in neurodegenerative conditions is largely unexplored. Microglia are the immune cells of the brain and play important homeostatic functions in health and disease. In this study, we show that administration of exogenous GM1 exerts a potent anti-inflammatory effect on microglia activated with LPS, IL-1β or upon phagocytosis of latex beads. These effects are partially reproduced by L-t-PDMP, a compound that stimulates the activity of the ganglioside biosynthetic pathway, while inhibition of ganglioside synthesis with GENZ-123346 increases microglial transcriptional response to LPS. We further show that administration of GM1 increases the uptake of apoptotic bodies and latex beads by microglia, as well as microglia migration and chemotaxis in response to ATP. On the contrary, decreasing microglial ganglioside levels results in a partial impairment in both microglial activities. Finally, increasing cellular ganglioside levels results in decreased expression and secretion of microglial brain derived neurotrophic factor (BDNF). Altogether, our data suggest that gangliosides are important modulators of microglia functions that are crucial to healthy brain homeostasis, and reveal that administration of ganglioside GM1 exerts an important anti-inflammatory activity that could be exploited therapeutically.