Gangliosides in the brain in adult Down’s syndrome and Alzheimer’s disease

Abstract

Quantitative analysis of total gangliosides and of ganglioside composition by HPTLC has been carried out on the gray matter of frontal cerebral cortex of six brains from Down's syndrome (DS) adults, six age-matched controls, six Alzheimer's disease (AD) adults, and six controls matched for age with the AD brains, as well as on three DS and six control cerebellum specimens. In addition, the analyses were carried out on specimens of corpus callosum of five adult DS and five control brains. No abnormalities were found in the gangliosides of DS corpus callosum. In DS frontal cortex, the concentration of total gangliosides was reduced, and there was a decrease in the fraction of GT1b and GD1b, and an increase in those of GT1a, GD3, GM1 and GM2; the ratio of total b-series to a-series gangliosides was decreased. Very similar abnormalities were found in the gangliosides of DS cerebellum. In AD frontal cortex, by contrast, the total gangliosides and their composition were normal by comparison with age-matched controls, with the minor exception of reductions in the fractions of GQ1b and GT1L. It is concluded that abnormalities in gangliosides exist in the brain in DS that are unrelated to AD-type pathology and may reflect developmental disturbances.

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

“…In contrast to the robust changes in the cortex, only slight changes in the ganglioside pattern were found in the cerebellum in the PSEN1 and APP/PSEN1 mutant lines (40). Alterations in cerebellar gangliosides have not been reported in the cerebellum of AD brains, although b-series cerebellar gangliosides are reduced in normal aging (29) and a reduction in total cerebellar gangliosides has been reported in patients with DS (25). Recently, Bernardo et al (40) reported ganglioside alterations in mixed cortical/ hippocampal tissue of mice lacking St8sia1, the gene that codes for GD3 synthase (GD3S), and in a doubletransgenic (APP Swe /PSEN1De9) mouse model of AD crossbred with GD3S 2/2 mice.…”

“…Figure 1 shows the structure and metabolism of gangliosides in the brain. Several earlier studies showed alterations in ganglioside metabolism in AD brain (23)(24)(25)(26)(27)(28)(29). This is manifested as reductions in gangliosides in the majority of brain regions, including the cerebral cortex, hippocampus, basal telencephalon, and frontal white matter, and especially in the frontal cortex and white matter (24).…”

“…Consistent with these changes, the ratio of total b-series to a-series gangliosides was reduced in DS brains. In contrast to the substantial changes in DS patients, the total gangliosides and their composition were normal in frontal cortex from patients with AD compared with age-matched controls, with the minor exception of reductions in the fractions of GQ1b and GT1L (25). Crino et al (26) also reported that concentrations of gangliosides in individuals with dementia of the Alzheimer type (DAT) were significantly lower than the concentrations in control brains.…”

Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

“…The patterns of ganglioside alterations in AD are very complex and differ according to age of onset and type of mutation, suggesting that different GSL-regulated events contribute to the onset of different AD forms. However, a consistent finding was a reduced ganglioside concentration (associated with altered ratios of a-series to b-series gangliosides) in the majority of brain regions of AD and dementia of the Alzheimer type-affected patients [101,102,[226][227][228][229][230] with respect to age-matched healthy controls. A reduced sulfatide content in AD post-mortem brain samples has also been reported [231,232].…”

Proteomic evaluation of intermediary metabolism enzyme proteins in fetal Down's syndrome cerebral cortex

“…A series of biochemical findings, including deteriorated glucose [3][4][5][6][7][8][9], lipid [10][11][12], purine [13][14][15], methionine/homocysteine [16][17][18] and folate [17,[19][20] metabolism have been reported but no systematic study on metabolic differences in fetal or adult DS brain has been conducted so far.…”