engleski

Composition and metabolism of gangliosides is altered in neural and non-neural tissue in Alzheimer's disease

The biological roles of gangliosides/glycosphingolipids (GSL) have been extensively studied and their involvement in key cellular events as well as their particularly important functions in animal brain tissue are well known. The idea that there are alterations in glycosphingolipid metabolism in Alzheimer's disease (AD) arose from biochemical studies of brain gangliosides pattern. Changes in content and composition of gangliosides and other membrane lipids in AD brain regions were documented by several groups, including ours. Observed specific alterations of ganglioside pattern in AD brains were mostly discussed as a consequence of: (a) neuronal cell degeneration, demyelination and gliosis ; (b) accelerated lysosomal degradation of gangliosides. Increased expression of lysosomal hydrolases in neuronal populations affected by amyloid pathology was indeed documented by other groups. This finding was explained as a proof for up-regulation of endosomallysosomal system in AD and was proposed to be an early marker of metabolic dysfunction related to primary AD etiopathogenesis. A speculation that alteration of ganglioside metabolism/catabolism occurs also in nonneural tissue in AD was further studied by our group. In our study the activity of several enzymes involved in ganglioside and sulfatide catabolism ( 13-galactosidase, 13-hexosaminidase, hexosaminidase A and arylsulfatase A) was analyzed in leukocytes and skin fibroblasts derived from individuals with AD and Down's syndrome (DS). Our results showed statistically significant increase in 13-galactosidase activity in AD and DS leukocytes in comparison with age-matched control leukocytes. Also, increased activity of 13-galactosidase and 13-hexosaminidase was observed in AD and fetal DS skin fibroblast cell line and age-matched controls obtained from commercial sources as well as in several DS and age-matched control skin fibroblast cultures established in our laboratory. Obtained results indicated that acceleration of at least some lysosomal catabolic pathways of gangliosides is present in AD and DS nonneural cells (leukocytes and skin fibroblasts). These findings raised several interesting questions: first, whether detected changes of glycosphingolipid metabolism in peripheral cells may present as peripheral biochemical markers in AD ; second, is there a change in transcriptional regulation of analyzed enzymes in AD ; third, are there mutations in genes coding for GSL biosynthetic/catabolic enzymes which may contribute to complex AD pathogenesis ; fourth, which other (epigenetic) events modify and cause altered enzyme activities in both AD and DS.

gangliosides; neurons; Alzheimer's disease

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