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Distinct roles for sphingolipids and glycosphingolipids at different stages of neuronal development

100%

Futerman A. H.

nr 2

Studies on the roles of sphingolipids (SLs) and glycosphingolipids (GSLs) at distinct stages of neuronal development have been performed using primary cultures of hippocampal neurons, which are unique among neuronal cultures inasmuch as they develop by a well-characterized and stereotypic sequence of events that gives rise to fully differentiated axons and dendrites. Our data demonstrate that SLs and GSLs play at least three distinct roles in regulating neuronal development, namely: (i) ceramide enhances the formation of minor neuronal processes from lamellipodia and the subsequent stage of axonogenesis; (ii) glucosylceramide synthesis, but not the synthesis of higher-order GSLs, is required for normal axon growth and for accelerated axonal growth upon stimulation by growth factors; and (iii) at both of these stages, ceramide at high concentrations can induce apoptotic cell death. Together, these observations are consistent with the possibility that minor process formation and apoptosis are regulated by ceramide-dependent signaling pathways, whereas axonal growth requires glucosylceramide synthesis, perhaps to support an intracellular transport pathway.

Brain spingolipids in hyperglycemia

26%

Car H. , Fiedorowicz A. , Prokopiuk S. , Bienias K. , Zendzian-Piotrowska M. , Chabowski A. , Kosacka I. , Tidhar R. , Futerman A. H. , Glombik K. , Basta-Kaim A.

tom 75

nr Supl.

Ceramide (Cer) and sphingomyelin (SM) are members of sphingolipid (SL) family. Their concentrationsin the brain undergo substantial changes in many pathologies. They are also important players in diabetes-linked brain dysfunctions, in which increased content of ceramides can be toxic to neurons. The aim of the study was to evaluate selected parameters of sphingolipids and insulin pathways in prefrontal cortex (PC) and hippocampus (H) of rats with experimentally induced hyperglycemia. STZ-rat model of type 1 diabetes and high fat diet model of insulin resistance were used. Analyses of studied parameters were performed by GLC, IHC and Elisa. We found the augmented levels of ceramides in H and PC and only minor in striatum and cerebellum of rats with STZ-induced diabetes. Similar expressions of Cer were confirmed by IHC. Myriocin, an inhibitor of an enzyme of ceramide de novo synthesis pathway, reduced ceramide generation in hyperglycemic brains, particularly in PC, which was reflected in altered Cer synthase activities. In addition, we reported the fluctuations in sphingomyelin levels in investigated structures. The level of insulin did not change in H and PC of STZ-treated rats. An expression of insulin receptor and its phosphorylated form decreased in both structures, but was restored after myriocin administration. Similarly, Akt and phosphorylated Akt changed in these structures suggesting important role of de novo Cer synthesis in intracellular pathways of insulin. In the rat model of high fat diet, which leads to insulin resistance, the sphingolipid pattern (Cer and SM) was altered in H and PC as well. Metformin, the drug of choice in diabetes type 2, influenced the content of the above SLs in these structures, suggesting the additional central activity of antidiabetic treatment. We conclude that ceramide and SM may be important mediators of diabetes- accompanied brain dysfunction.