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

Abstract

Gangliosides 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 antiinflammatory 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.

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

“…The ability of gangliosides to interact with amyloidogenic proteins such as Aβ, α-synuclein and mHTT, and to modulate how these proteins fold and misfold might be particularly important from a mechanistic and therapeutic perspective, and deserves close attention. Potent anti-inflammatory effects of GM1 on microglia have also been recently described ( Galleguillos et al, 2020 ). As aberrant and chronic microglia activation and neuroinflammation are important features of many neurodegenerative disorders ( Perry et al, 2010 ), this property of GM1 could further contribute to ameliorate neurodegenerative conditions.…”

Effects of Early-Life Stress, Postnatal Diet Modulation and Long-Term Western-Style Diet on Peripheral and Central Inflammatory Markers

“…Both the type and quantity of fatty acids is known to affect microglia physiology directly as well as indirectly via hormones and the gut [88]. For example, gangliosides, which are present in Nuturis ® , have been shown to have anti-inflammatory effects in microglia activated with lipopolysaccharide [89].…”

Excessive aggression, ADHD- and ASD-like phenotypes in TPH2- and brain ganglioside-deficient mice

“…They are ubiquitous in cell membranes in all vertebrates, performing many functions, including protein organization, signaling, and cell adhesion -39 - . Gangliosides are predominantly found in the CNS, where they play critical roles in development and function (Bowser et al, 2019;Galleguillos et al, 2020;Schnaar et al, 2014). The majority of brain gangliosides consist of derivatives of ganglioside GM3 (Ishii et al, 1999).…”

“…The mechanisms underlying a link between the path physiology of neurodevelopmental disorders and dysregulated brain gangliosides implicate neuroinflammation as a risk factor of these pathologies Matta et al, 2019;Meyer, 2013), as gangliosides are known to regulate immune responses in which they have an anti-inflammatory role (Galleguillos et al, 2020;Sipione et al, 2020). Specifically, gangliosides have been shown to regulate the effects of tumour necrosis factor (TNF) (Tagami et al, 2002), microglial and platelet activation Sotnikov et al, 2013), nitric oxide synthase (NOS2), and ICAM-1 and MCP-1-mediated signalling (Kim et al, 2002;Ryu et al, 2002).…”

“…Specifically, gangliosides have been shown to regulate the effects of tumour necrosis factor (TNF) (Tagami et al, 2002), microglial and platelet activation Sotnikov et al, 2013), nitric oxide synthase (NOS2), and ICAM-1 and MCP-1-mediated signalling (Kim et al, 2002;Ryu et al, 2002). For microglia treated with lipopolysaccharide (LPS), interleukin-1β (IL-1β) or ATP, gangliosides have been shown to have anti-inflammatory effects (Galleguillos et al, 2020). Moreover, neuroinflammation and neuro-immune system dysregulation are particularly well established as clinical features of ASD (Gevezova et al, 2020;Siniscalco et al, 2018).…”