Gangliosides in the human brain development and aging.

In this study, brain gangliosides in prenatal and postnatal human life were analyzed. Immunohistochemically, the presence of "c"-pathway of gangliosides (GQ1c) in embryonic brain was only recorded at 5 weeks of gestation. Biochemical results indicated a twofold increase in human cortex ganglioside concentration between 16 and 22 weeks of gestation. The increasing ganglioside concentration was based on an increasing GD1a ganglioside fraction in all regions analyzed except cerebellar cortex, which was characterized by increasing GT1b. In this developmental period, GD3 was found to be localized in the ventricular zone of the cortical wall. After birth, GD1b ganglioside in neuropil of granular cell layer corresponding to growing mossy fibers was expressed in cerebellar cortex. Between birth and 20/30 years of age, a cerebral neocortical difference of ganglioside composition was observed, characterized by lowest GD1a in visual cortex. Analyzing the composition of gangliosides in cortical regions during aging, they were observed to follow region-specific alterations. In frontal cortex, there was a greater decrease in GD1a and GM1 than in GT1b and GD1b, but in occipital (visual) cortex there was no change in individual gangliosides. In hippocampus, GD1a moderately decreased, whereas other fractions were stable. In cerebellar cortex, GD1b and GT1b fractions decreased with aging.     

Changes of brain gangliosides in chicken and mice during heterothermic development

Developmental profiles of brain gangliosides of chicken and mice were correlated to thermo-biological parameters. In parallel with an increasing body temperature and resistance to cold stress (within the first 11 postnatal days) the brain gangliosides change to a less polar pattern, indicated by a higher proportion of oligosialogangliosides.     

The biosynthesis of gangliosides. Labelling of rat brain gangliosides in vivo

1. After injection of [6-(3)H]glucosamine into 8-day-old rats it was found that all the major brain gangliosides and their sialyl groups were labelled at essentially the same rate, except the hematoside, which was the least labelled. In 18-day-old rats it was found that the two major gangliosides with the sialyl (2-->8)-sialyl linkage, and their sialyl groups were more labelled than the hematoside, the Tay-Sachs ganglioside, the other two major gangliosides and their respective sialyl groups. 2. No difference was found in any of the cases studied between the specific radioactivities of the neuraminidase-resistant and -labile sialyl groups belonging to the same ganglioside. The same was found for the specific radioactivities of the galactosyl groups proximal and distal to the ceramide moiety of total brain gangliosides from rats injected with [U-(14)C]glucose. From this it was concluded that partial turnover of the ganglioside molecule does not occur. 3. A model for the synthesis of gangliosides is presented that accounts for results from previous experiments in vitro and the lack of precursor-product relationships observed in experiments in vivo.     

Mitochondria: dynamic organelles in disease, aging, and development

Mitochondria are the primary energy-generating system in most eukaryotic cells. Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis. Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues. However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms. Clearly, much about the basic biology of mitochondria remains to be understood. Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease.     

N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease

Oxidative stress has been implicated in the pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM). N epsilon-carboxymethyllysine (CML) is an advanced glycation end product (AGE) recently found to be associated with oxidative stress mechanisms. Using immunocytochemical methods we examined the distribution of CML in brain tissue from AD and DM subjects and aging controls. CML reactivity was present in the cytoplasm of neurons, but there were marked differences in the intensity of expression, number of cells, and topographical distribution. CML expression was higher in hippocampus than in frontal and temporal cortex. In the hippocampus, neuronal and, to an extent, glial expression was more marked in CA3 and CA4 than in CA1 and CA2. In AD, CML was found to be coexpressed with tau protein, showing the similar neurofibrillary tangle shape, as well as in neuritic plaques but not in the core of amyloid plaques. We noted an increasing degree of CML expression such that the highest reactivity was evident in those with both AD and DM, followed by AD, DM, and aging controls. There was an inverse relationship between Braak staging and topography of CML expression. Although DM cases did not show Abeta deposition or neurofibrillary tangles, these findings suggest increased CML expression is not limited to AD. Nonetheless, high CML expression in AD with coexistent DM suggests there are additive effects compared with AD alone. It is plausible that the microangiopathy also associated with DM could worsen AD pathogenesis.     

Abnormal gangliosides in Tay-Sachs disease, Niemann-Pick's disease, and gargoylism

The molar ratios of N-acetyl neuraminic acid, hexose, hexosamine, and sphingosine have been determined for the abnormal ganglioside in Tay-Sachs disease that was previously detected as a fast-moving band in thin-layer chromatography, and in two abnormal fast-moving bands of gangliosides from the cortex and white matter of the brain in cases of gargoylism and Niemann-Pick's disease. The fastest-moving ganglioside band in these two conditions contains neither hexosamine nor glucose.     

Lipid peroxidation in aging brain and Alzheimer's disease

Lipid peroxidation is one of the major outcomes of free radical-mediated injury that directly damages membranes and generates a number of secondary products, both from fission and endocyclization of oxygenated fatty acids that possess neurotoxic activity. Numerous studies have demonstrated increased lipid peroxidation in brain of patients with Alzheimer's disease (AD) compared with age-matched controls. These data include quantification of fission and endocyclized products such as 4-hydroxy-2-nonenal, acrolein, isoprostanes, and neuroprostanes. Immunohistochemical and biochemical studies have localized the majority of lipid peroxidation products to neurons. A few studies have consistently demonstrated increased cerebrospinal fluid (CSF) levels of isoprostanes in AD patients early in the course of their dementia, and one study has suggested that CSF isoprostanes may improve the laboratory diagnostic accuracy for AD. Similar analyses of control individuals over a wide range of ages indicate that brain lipid peroxidation is not a significant feature of usual aging. Quantification of isoprostanes in plasma and urine of AD patients has yielded inconsistent results. These results indicate that brain lipid peroxidation is a potential therapeutic target in probable AD patients, and that CSF isoprostanes may aid in the assessment of antioxidant experimental therapeutics and the laboratory diagnosis of AD.     

Phylogenetic and regional variations in brain gangliosides of tetrapods.

1. Ganglioside patterns were analyzed from four neural tissues (medulla, midbrain, forebrain and retina) in a representative from each of the four tetrapod classes. 2. Regional variations in ganglioside patterns were noted within some species, but differences were greater across phylogenetic lines. 3. These results suggest that evolutionary history plays a greater role than neural differentiation in the expression of brain ganglioside patterns.     

Exercise, cognition, and the aging brain.

We provide a brief review of the literature on exercise effects on brain and cognition. To this end, we focus on both prospective and retrospective human epidemiological studies that have examined the influence of exercise and physical activity on cognition and dementia. We then examine the relatively small set of human randomized clinical trials that have, for the most part, focused on exercise training effects on cognition. Next, we discuss animal research that has examined the molecular, cellular, and behavioral effects of exercise training. Finally, we conclude with a summary and brief discussion of important future directions of research on fitness cognition and brain.     

Cortical distribution of gangliosides in Alzheimer's disease.

In Alzheimer's disease, all ganglio-series gangliosides (GM1, GD1a, GD1b and GT1b) were found to be decreased in temporal and frontal cortex, and nucleus basalis of Meynert. In addition, in Alzheimer's disease simple gangliosides (GM2, GM3) were elevated in frontal and parietal cortex, possibly correlating to accelerated lysosomal degradation of gangliosides and/or astrogliosis occurring during neuronal death.     

Alcohol, in a single pharmacological dose, decreases brain gangliosides

Alcohol penetrates into cell membranes, fluidizing and disordering the microenvironment. Here we report that associated with the disordering is a reduction of the normal level of brain gangliosides of adult male rats. The maximum decrement occurred in all major classes of gangliosides at 4 to 8 hours after a single pharmacological dose (3 gm/kg, IP). Because gangliosides have diverse, important functions in cell membranes, this effect of alcohol might be a basis for some of its intoxicating and addicting properties.     

The biosynthesis of brain gangliosides. Ganglioside-glycosylating activity in rat brain neuronal perikarya fraction.

Rat brain homogenate and the synaptosmal and neuronal perikarya fractions from 17-day-old rats were compared for their activities in sialosylating endogenous gangliosides and transferring N-acetylneuraminic acid and galactose to several glycolipids in vitro. The sialosylation of endogenous gangliosides and the activities of sialosyltransferases acting either on lactosylceramide or haematoside as acceptors, as well as galactosyltransferase acting on Tay-Sachs ganglioside as acceptor, were between 3-and 12-fold higher in the neuronal perikarya fraction than in whole homgenate on a protein or ganglioside basis. The activities found in the synaptosomal fraction were negligible. No evidence was found to indicate that the low activities in this fraction were due to the presence of inhibitors of the transfer activities or to inacessibility of the substrates to their respective enzymes. These findings, and the time course of labelling of gangliosides of the neuronal perikarya and synaptosomes from rats that received an injection of N-[3H]acetylmannosamine, indicate that the main cellular site of glycosylation of neuronal gangliosides is in the neuronal perikarya.     

Functional relationship between ammonia and gangliosides in brain

The functional significance of ammonia production in brain under physiological or pathological conditions is not clearly known. NH₄ ⁺ stimulates Na⁺, K⁺ activated ATPase causing stabilization of neuronal membranes of which gangliosides are major structural components. Moreover ammonia is known to inhibit lysosomal enzymes which include enzymes degrading gangliosides. Gangliosides have been shown to stimulate neuritogenesis in neuronal cultures and prevent the damage of the neurons from glutamate toxicity particularly in areas of brain ischemia. Hyperammonemia without any behavioural changes was induced in experimental rats by intraperitoneal administration of either a single dose (0.8 mmol/100 g wt.) or by six hourly doses (0.6 mmol/100 g wt.) of ammonium acetate. An increase in the content of gangliosides along with a rise in the content of GD_1A and GD_1B without any change in -galactosidase and N-acetylhexosaminidase was observed in cerebral cortex, cerebellum, and brain stem, following the administration of single dose of ammonium acetate. Gangliosides, after extraction from the different brain regions, were estimated by the thiobarbituric acid method and expressed in terms of sialic acid. Individual gangliosides were separated and estimated by thin layer chromatography using resorcinol as the staining agent. These results suggest that ammonia production in the neuronal pathways in brain either as a result of repeated stimulation under physiological conditions or as a result of focal ischemia or injury, may likewise cause an increase in the content of gangliosides which may help in neuritic growth (physiological conditions facilitating synaptic plasticity) and may exert a protective effect on the neurons in the ischemic area against glutamate toxicity.Former Professor of Biochemistry, OMC, Hyderabad.