The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease

Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and beta-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.