Gangliosides are sialic acid-containing glycosphingolipids that are most abundant in the nervous system. Heterogeneity and diversity of the structures in their carbohydrate chains are characteristic hallmarks of these lipids; so far, 188 gangliosides with different carbohydrate structures have been identified in vertebrates. The molecular structural complexity increases manifold if one considers heterogeneity in the lipophilic components. The expression levels and patterns of brain gangliosides are known to change drastically during development. In cells, gangliosides are primarily, but not exclusively, localized in the outer leaflets of plasma membranes and are integral components of cell surface microdomains with sphingomyelin and cholesterol from which they participate in cell-cell recognition, adhesion, and signal transduction. In this brief review, we discuss the structures, metabolism and functions of gangliosides.

The extracellular accumulation of amyloid beta proteins (Abetas) in neuritic plaques is one of the hallmarks of Alzheimer's disease (AD). The binding of Abetas to extracellular membranes (ECMs) is a critical step in developing AD. Abetas bind to many biomolecules, including lipids, proteins, and proteoglycans (PGs). PGs play several roles in amyloid formation, including promoting the aggregation of Abetas into insoluble amyloid fibrils, which contributes to the increased neurotoxicity of Abetas. Although Abetas readily self-aggregate to form amyloid fibrils in vitro, their binding to PGs and heparin enhances amyloid aggregation and fibril formation. The sulfate moiety in glycosaminoglycans (GAGs), the carbohydrate portion of PGs, is necessary for the formation of amyloid fibrils; no fibrils are observed in the presence of hyaluronic acid (HA), a nonsulfated GAG. PGs and Abetas are known to colocalize in senile plaques (SPs) and neurofibrillary tangles (NFTs) in the AD brain. The binding site of PGs to Abetas has been identified in the 13-16-amino-acid region (His-His-Gln-Lys) of Abetas and represents a unique target site for inhibition of amyloid fibril formation; His13 in particular is an important residue critical for interaction with GAGs. The sulfate moieties of GAGs play a critical role in the binding to Abetas and enhance Abeta fibril formation. Low-molecular-weight heparins (LMWHs) can reverse the process of amyloidosis to inhibit fibril formation by blocking the formation of beta-plated structures, suggesting a possible therapeutic approach using LMWHs to interfere with the interaction between PGs and Abetas and to arrest or prevent amyloidogenesis.

Gangliosides are sialic acid-containing glycosphingolipids abundant in the central nervous tissues. The quantity and expression pattern of gangliosides in brain change drastically during early development and are mainly regulated through stage-specific expression of glycosyltransferase (ganglioside synthase) genes. It is still unclear, however, how the transcriptional activation of glycosyltransferase genes is regulated during development. In this study, we investigated the epigenetic regulation of two key glycosyltransferases, N-acetylgalactosaminyltransferase I (GA2/GM2/GD2/GT2-synthase) and sialyltransferase II (GD3-synthase), in embryonic, post-natal, and adult mouse brains. Combined bisulfite restriction analysis assay showed that DNA methylation in the 5′ regions of these glycosyltransferase genes was not associated with their expression patterns. On the other hand, chromatin immunoprecipitation assay of both glycosyltransferase genes showed that their histone H3 acetylation was highly correlated to their mRNA expression levels during development. In fact, we confirmed that the expression patterns of gangliosides and glycosyltransferases in neuroepithelial cells were changed after treatment with a histone deacetylase inhibitor, sodium butyrate. Our studies provide the first evidence that efficient histone acetylation of the glycosyltransferase genes in mouse brain contributes to the developmental alteration of ganglioside expression.

Background: To study the effects of a pre-germinated brown rice diet (PR) on diabetic neuropathy in streptozotocin (STZ)-induced diabetic rats.

We have devised an analytical method for the determination of fatty acid composition of erythrocyte membrane sphingomyelin by chemical ionization mass spectrometry combined with capillary column gas-liquid chromatography. Fatty acid composition of erythrocyte membrane sphingomyelin from 8 patients with adrenoleukodystrophy (ALD) and 16 healthy controls were examined by this method. The ratio of hexacosanoic acid (C26:0) to docosanoic acid (C22:0) in erythrocyte membrane sphingomyelin from ALD patients was 2.6-fold higher than that of the controls. This result suggests that biochemical diagnosis of ALD is possible by the analysis of fatty acid composition of erythrocyte membrane sphingomyelin. Furthermore, it demonstrates that biochemical abnormality in ALD is the generalized abnormal metabolism of very long-chain saturated fatty acids.

Previous studies from our laboratory indicated that pre-germinated brown rice (PR) contained certain unknown bioactive lipids that activated two enzymes related to diabetes: Na 1 /K 1 ATPase and homocysteine-thiolactonase. In this paper, we report on the isolation and structural characterization of the activator lipids from PR bran as acylated steryl glucosides (ASGs). The activator lipid was isolated by silica gel column chromatography, and its chemical structure was determined by NMR, GC-MS, and tandem mass spectrometry. We demonstrated that the bioactive component consists of a mixture of acylated steryl b-glucosides. #8-cholesterol and 2-hydroxyl stearic acid were identified as constituents of ASGs. The steryl glucosides (SGs) subsequent to alkaline hydrolysis lost this enzyme activator activity. Soybean-derived ASGs were not active. This activity may be quite peculiar to PR-derived ASGs. Our findings suggest that the molecular species of ASG may play an important contributing role in the anti-diabetic properties of a PR diet.-Usuki, S., T. Ariga, S. Dasgupta, T.

We studied the metabolism of radioactive stearic acid by cultured skin fibroblasts from patients wtih adrenoleukodystrophy (ALD) and its variant, adrenomyeloneuropathy (AMN), to clarify the mechanism of the increased content of very long chain saturated fatty acids in cholesterol esters and sphingolipids, which are known to be the characteristic biochemical changes in ALD and AMN. A substantial amount of hexacosanoic acid (C26 : 0) wa synthesized from stearic acid by ALD and AMN fibroblasts, whereas only a trace amount of hexacosanoic acid was synthesized by control fibroblasts. This indicates that the primary biochemical defect in ALD and AMN may involved the elongation system of very long chain fatty acids.

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