# Gangliosides (GA) and brain development

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Gangliosides (GA) and brain development
Key Points
* Gangliosides are sialic acid-containing glycosphingolipids.
* The high presence of specific Gangliosides in human breast milk and the brain indicates the importance of their role in the developing human.
* The role of Gangliosides in brain development includes
   * stimulating neuronal cell outgrowths - axons and dendrites
   * formation of synapses - Gangliosides are most concentrated at nerve endings where the connections between brain cells are formed
   * function of the synaptic connections including neurotransmitter processing, recognition of neurotransmitters, restoration of the synapse
   * stabilisation of synaptic connections for information storage as the basis of memory
   * myelination for insulating the neuronal cell outgrowths and for maintaining the integrity of axons for signal transmission.
* Dietary Gangliosides impact tissue composition of Gangliosides by being incorporated into cell membranes around the body, and in particular the brain.
* New research shows that dietary supplementation improves learning and memory and increases cognitive performance.
Introduction
Gangliosides are complex glycolipids which are important components of cell membranes found throughout the body. They are involved in cell structure and function, in particular in the brain. The fastest rate of Ganglioside synthesis and accumulation in the developing brain occurs early in life - during fetal and postnatal development - during the periods of dendritic branching and new synapse formation.
Gangliosides occur naturally in our diet in foods such as dairy products, some meats and eggs. They are particularly high in human breast milk. Pre-clinical research has shown that dietary Gangliosides can be absorbed and are transported to different sites in the body; gut, blood, brain and eye tissue. While there are only a few human supplementation studies, it has been noted that the brains of breastfed babies contain higher levels of Gangliosides than brains from non-breastfed babies. Breastmilk contains higher levels of Ganglioside than breastmilk substitutes suggesting dietary Gangliosides may be an important nutritional component especially in early childhood when the brain is still developing and relies on dietary supply of key nutrients.
What are Gangliosides?
Gangliosides were first identified over a century ago and were named after the ganglion cells of the brain, from which they were first isolated; however they are also found in other membranes throughout the body. Gangliosides are a group of complex glycolipid compounds that differ in the fatty acid and sugar components of their molecules.
Gangliosides are negatively charged glycosphingolipids (sugar containing sphingolipids) which are a subgroup of membrane lipids called sphingolipids. What distinguishes Gangliosides from other glycosphingolipids is that they contain the sugar sialic acid (N-acetylneuraminic acid, NANA) which carries a charge at physiological pH and may be responsible for some of the properties and activities of Gangliosides.
Where are Gangliosides found in the body?
Gangliosides are principal membrane constituents of vertebrate cells. Gangliosides make up 10% of the total lipid mass in the brain. They are the major glyco-compounds of neurons and carry most of the sialic acid in their oligosaccharides chains found in the brain.
Brain growth and maturation are associated with an increase in Ganglioside concentration. The Ganglioside distribution in the human brain also changes significantly during development. The concentration increases approximately 3 times from the 10th gestational week to about 5 years of age. The mature brain contains about 20 times greater amounts of Gangliosides than other tissues; Ganglioside concentration in brain grey matter is 15 times that of other organs such as liver, lung and spleen and 500 times greater than the intestinal mucosa;. Within the brain, cerebral grey matter contains considerably higher concentrations, around 3 times the amount of Gangliosides compared to white matter.
Role of Gangliosides in brain development
Ganglioside synthesis is essential for the development of a stable central nervous system, possibly by promoting interactions between axons, or neurite outgrowths, and glial cells. They also contribute to neural growth, modulate neural functions and are involved in neuritogenesis, information storage and the process of memory formation. Gangliosides play a key role in the formation of synapses between neural cells and also during the process of neural transmission by facilitating neurotransmitter molecule binding to synaptic membranes. Gangliosides are also presumed to act as substrates for neural layer formation which generates higher cognitive functions in the brain.
Brain Structure
The expression of Gangliosides is abundant in neural cells and drastically changes during development of the central nervous system (CNS). Therefore, Gangliosides have been suggested to play an important role in the development of the nervous system. At the cellular level, Gangliosides are found in the outer layer of the lipid bilayer of the brain cell membrane. Ganglioside accretion is highest during the period of dendritic branching and synaptogenesis, which occurs in late fetal development and early childhood.
Gangliosides are required for axonal and dendritic growth, increasing both neuritogenesis and synapse formation. Research has shown that neuronal cells produce more neurite outgrowths when exogenous Gangliosides are available, and in vitro studies demonstrate that Gangliosides derived from milk can enhance neuritogenesis. Not only are the number of neurite outgrowths enhanced, but also the length of the processes and the number of branches are increased in the presence of Gangliosides.
Gangliosides are concentrated in the plasma membrane of nerve cells, especially in the region of nerve endings and dendrites. Gangliosides are transported along the axon and the dendrite branches to the nerve endings so that relatively high concentrations are found in the synaptic plasma membrane. One of the key roles of Gangliosides in brain function is in the formation of the synaptic connections between neurons. The main function seems to be to facilitate transmission of neural impulses across brain synapses, in part attributable to the sialic acid portion of the molecule.
Gangliosides are also involved in the process of myelination of axons and dendrites helping to protect nerve fibres and to maintain the integrity of brain cell connections and nerve transmission. When Ganglioside metabolism is ineffective or there is a deficiency of Gangliosides, axonal degeneration as well as reduced myelination or demyelination occurs;. This further demonstrates the role of Gangliosides in central myelination and stabilisation of brain function.
Brain Function
Gangliosides are involved in the basic tasks of the neuron which make up cognitive function including the transmission of messages around the neural circuits (synaptic transmission - neurotransmitter processing and restoration of the neuron cell post signalling) and information storage (formation of memory and learning);.
Neurotransmission
It is thought that Gangliosides play a role in neural transmission because they are components of the plasma membrane and are enriched in the synaptic junction. As such they are known to modulate ion channel function and so are involved in the release of neurotransmitters. They are also important in the post-synaptic neuron where they play a role in receptor signal recognition and response. These two functions are essential for the successful transmission of nervous impulses.
Gangliosides are localized in clusters on neuronal, and especially in the outer layer of synaptic, membranes, in the vicinity of membrane-bound calcium pumps. They possess special physicochemical properties particularly in their interaction with calcium; Ca2+ ions are important mediators in neuronal responses. Gangliosides bind Ca2+ ions via electrostatic interactions between the ions and sialic acid residues on the Gangliosides. Calcium is required for synaptic transmission and probably activates second messenger pathways.
Improved learning ability and memory retention
Gangliosides have been hypothesised to be involved in the formation of memory. Research in animal models has shown that exogenous Gangliosides can enhance the learning ability and memory retention at different ages. It has also been reported that exogenous and orally administered Gangliosides accelerate the growth of brain cells, repair damaged nerve cells, build up memory and prevent cerebral atrophy in children with impaired brain function such as cerebral palsy.
Ganglioside functions for visual development
Gangliosides are also important for visual function; the retina is a part of the CNS, and the localization of Gangliosides in the retina may also be crucial to the structure of photoreceptor membranes during development. Gangliosides stabilize the retina membrane, protect against injuries and enhance visual function after retinal damage. Gangliosides may play a major role in membrane structure of photoreceptor cells by increasing membrane permeability and fluidity, as well as through activity of signalling molecules. Photoreceptor cells contain approximately 25% of the total Gangliosides present in the whole retina.. Animals fed dietary Gangliosides or long chain PUFA had increased total retinal Ganglioside content during retinal development.
Dietary sources of Gangliosides
Dietary sphingolipids, including Gangliosides, are ingested as part of animal products such as dairy, meat and eggs. However, plants are not a source of Gangliosides as they lack the biochemical means to synthesise sialic acid. Daily intake of sphingolipids has been calculated to be 0.3 -0.4g/day but Gangliosides only make up a small percentage of this figure.
Gangliosides in milk are almost exclusively associated with the membrane fraction of the milkfat globule. In human milk, the total concentration of Gangliosides is higher in colostrum than in later milk and range from 10 – 16 mg/L;. In cows’ milk this also occurs where the total concentration of Gangliosides is highest in colostrum. This is then followed by a drop in concentration for a period and then a rise again in late lactation;.
Effect of dietary Gangliosides on nutritional status
It has also been shown that dietary Gangliosides increase the total Ganglioside content in the brain, plasma and intestinal mucosa. Ganglioside composition, ie the types of Gangliosides, is not affected however. This indicates that dietary Gangliosides provide the building blocks but may be modified to meet the needs of the tissue at each specific stage of development.
A recent infant study has provided further evidence that dietary Gangliosides influence Ganglioside status. This study compared the effects of breastfeeding, or feeding standard infant formula or infant formula fortified with Gangliosides from complex milk lipids to more closely match breastmilk levels. After 4.5 months, serum Ganglioside levels were significantly lower in the infants fed standard infant formula which is likely to be due to the differences in Ganglioside intake. This is the first study to report human infant serum Ganglioside levels after dietary supplementation and indicates that supplementation results in serum Ganglioside levels more closely resembling those of breastfed infants.
Effect of dietary Ganglioside intake on brain development
Availability of dietary Gangliosides is now thought to be important for the developing brain. This is based on observations that infants fed human milk have been shown to have higher levels of brain Gangliosides and glycoprotein sialic acid concentrations than infants fed infant formula which contains lower levels of Gangliosides. It is suggested that breastfed infants have improved cognitive development compared to infants fed some infant formula products, and enhanced Ganglioside availability may lead to increased synaptogenesis and differences in neurodevelopment. Recent research has also shown that the types of Gangliosides most commonly found in milk (and circulating in the blood) are able to be transferred by the human placenta and made available to the developing foetus at a time when brain accretion of Gangliosides is very high, and that increased availability of dietary Gangliosides during pregnancy increases neonatal brain Ganglioside content.
Evidence suggests that Gangliosides play a role in memory formation, learning and memory retention, and behaviour. Recent research also suggests that Ganglioside supplementation in very young animals can impact on the rate of learning and memory however one study showed that feeding Gangliosides only up to weaning had no impact on later learning or memory, suggesting that dietary Gangliosides continue to be relevant after the weaning stage.
A recent study has suggested that dietary Gangliosides can help support normal cognitive development in infants. The double blind, placebo controlled study involved normal healthy term infants receiving standard infant formula or a Ganglioside-supplemented infant formula up to 6 months of age The Ganglioside fortification was to more closely match the intake of breastfed infants which may provide some advantages for cognitive development. There were statistically significant increases in scores for hand-eye coordination and performance IQ as well as total development or IQ score in the Ganglioside-supplemented group. Overall results for the Ganglioside-supplemented group were comparable to those for a breastfed reference group. There were no significant differences for some other scores such as in locomotor score, social interaction, and hearing and language between the two formula groups. This may be because these aspects of development are not sufficiently progressed at that age to pick up small differences in a study this size, or that dietary Gangliosides have specific roles in cognitive development and complementary nutrients are required to enhance other aspects of cognitive development and performance, such as DHA.
Conclusion
Gangliosides are complex glycolipid molecules with a variety of important roles within the body, based on knowledge of brain cell composition and evidence that they have been strongly associated with neural functioning. Observations from human studies suggest that the availability of dietary Gangliosides has an impact on brain composition which may contribute to the improved cognitive development reported for breast-fed vs. formula fed babies. Gangliosides appear to play both a structural and functional role in the brain, and evidence is accumulating from animal trials and human research suggesting that dietary Gangliosides improve learning and memory, and brain performance during critical periods of development. Therefore Gangliosides should be considered an important nutrient to support brain development in early childhood.

## References and notes

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* ↑ Yamashita T, Wu YP, Sandhoff R, Werth N, Mizukami H, Ellis JM, Dupree JL, Geyer R, Sandhoff K and Proia RL. 2005. Interruption of gangliosides synthesis produces central nervous system degeneration and altered axon-glial interactions. PNAS. 102(8):. pp. 2725-2730.
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* ↑ Park EJ, Suh M & Clandinin MT (2005a) Dietary ganglioside and long-chain polyunsaturated fatty acids increase ganglioside GD3 content and alter the phospholipid profile in neonatal rat retina. Investigative Ophthalmology & Visual Science 46,2571-2575.
* ↑ Park EJ, Suh M & Clandinin MT (2005a) Dietary ganglioside and long-chain polyunsaturated fatty acids increase ganglioside GD3 content and alter the phospholipid profile in neonatal rat retina. Investigative Ophthalmology & Visual Science 46,2571-2575.
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* ↑ Gurnida D, Rowan AM, Idjradinata P, Muchtadi D, Sekarwana N. Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants. Early Human Development, 2012, 88:595-601. DOI 10.1016/j.earlhumdev.2012.01.003.
* ↑ Wang B, McVeagh P, Petocz P, Brand-Miller J. (2003) Brain gangliosides and glycoprotein sialic acid in breastfed compared with formula-fed infants. American Journal of Clinical Nutrition 78,1024-9.
* ↑ Horwood LJ, Darlow BA, Mogridge N. Breast milk feeding and cognitive ability at 7–8 years. Arch Dis Child Fetal Neonatal Ed 2001;84:F23–7.
* ↑ Wang B, McVeagh P, Petocz P, Brand-Miller J. (2003) Brain gangliosides and glycoprotein sialic acid in breastfed compared with formula-fed infants. American Journal of Clinical Nutrition 78,1024-9.
* ↑ Mitchell M, Henare K, Lowe E, Naylor M, Fong B, & McJarrow P. (2012). Transfer of gangliosides across the human placenta. Placenta, 33,312-316.
* ↑ Gustavsson M, Hodgkinson SC, Fong B, Norris C, Guan J, Krageloh CU, Breier BH, Davison M, McJarrow P, Vickers MH. Maternal supplementation with a complex milk lipid mixture during pregnancy and lactation alters neonatal brain lipid composition but lacks effect on cognitive function in rats. Nutr Res. 2010 Apr;30(4):279-89.
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* ↑ Wainwright PE, Lomanowska AM, McCutcheon D, Park EJ, Clandinin MT & Ramanujam KS (2007). Postnatal dietary supplementation with either gangliosides or choline: effects on spatial short term memory in artificially-reared rats. Nutritional Neuroscience 10,67-77.
* ↑ Gurnida D, Rowan AM, Idjradinata P, Muchtadi D, Sekarwana N. Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants. Early Human Development, 2012, 88:595-601. DOI 10.1016/j.earlhumdev.2012.01.003.
* ↑ Horwood LJ, Darlow BA, Mogridge N. Breast milk feeding and cognitive ability at 7–8 years. Arch Dis Child Fetal Neonatal Ed 2001;84:F23–7.
* Fong B, Norris C, Lowe E, Vickers M, McJarrow P. Dietary supplementation of rats during pregnancy with a dairy derived lipid product significantly increases brain gangliosides in two day old pups. ISSFAL, Kansas, US, May 2008.
* Karim M & Wang B.(2006) Is Sialic acid in mlk food for the brain. CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources, No. 018. www.cababstractsplus.org/cabreviews