Sphingosine kinases and NPC1 decrease would contribute to altered function in old hippocampal neurons.

LEANDRO G ALLENDE; MARÍA FLORENCIA HARMAN; MAURICIO GERARDO MARTÍN

Congreso; XXXIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

It is now recognized that sphingolipid metabolites regulate many cellular processes important for health and disease. One of the most important of these metabolites is sphingosine-1-phosphate produced by two sphingosine kinase isoenzymes, SphK1 and SphK2.Among its roles, Sphk1 and Sphk2 have been implicated in neuronal function and memory formation. In hippocampal neurons, SphK1 participates in excitatory synaptic transmission and has profound effects on spatial learning. SphK1 is activity-dependent recruited to presynaptic terminals and promotes neurotransmitter release. Decreased levels of Sphk1 have been also associated to sphingosine accumulation leading to defects in endocytic trafficking. In the nucleus, SphK2 regulates gene transcription of memory genes by producing S1P, which acts as an endogenous inhibitor of histone deacetylases.Our results show that during aging, the levels of Sphk1 and Sphk2 are dramatically decreased in mouse hippocampus. According to these data, the accumulation of sphingosine was observed in hippocampal neurons aged in vitro. Furthermore, decreased expression of the npc1 (Niemann Pick C1) gene, required for intracellular cholesterol redistribution and one of the Sphk2 targets, was found in the hippocampus of old mice. All these results suggest that defects of neuronal function during aging would be due, at least in part, to deficits in S1P signaling and endocytic defects mainly consequence of cholesterol accumulation in the endolisosomal compartment.