Effects of myriocin and FTY720 on gene expression of sphingolipid metabolism enzymes in animal model of Alzheimer’s disease

INTRODUCTION: Sphingolipid imbalance has been observed in Alzheimer’s disease (AD) (accumulation of the pro-apoptotic ceramide, and loss of the protective sphingosine-1-phosphate – S1P) being correlated with the progress of neurodegeneration. Deregulated sphingolipid homeostasis may lead to neuronal death. Therefore enzymes regulating sphingolipid metabolism gain attention as highly promising targets in AD research/therapy. AIM(S): We examined the influence of myriocin and FTY720 on gene expression of enzymes metabolizing ceramide/sphingosine-1-phosphate in a mouse transgenic AD model. METHOD(S): mRNAs were measured with real-time PCR in the cerebral cortex of 6-months old FVB mice overexpressing human Aβ precursor protein (APP) treated with myriocin, a ceramide biosynthesis inhibitor, and FTY720 a sphingosine analog and sphingosine-1-phosphate receptor modulator. RESULTS: Myriocin has increased the expression of ceramidases ACER2 and -3, ceramide kinase (CERK), sphingosine kinase 2 (SPHK2) and S1P receptors (S1PR1 and -5) in APP mice. These results suggest a metabolic shift from ceramide towards the survival-promoting ceramide-1-phosphate and S1P. However, both Bcl-2 and Bax were increased, leaving the question open. The mock-transfected animals seemed to respond to treatment with a shift towards ceramide accumulation and dephosphorylation of S1P into sphingosine. FTY720 treatment of APP animals increased mRNA levels of ceramide synthases (CERS2 and 6), SPHK1 and 2, and proteins from Bcl-2 family. CONCLUSIONS: Our results suggest that myriocin and FTY720 treatment may lead to widespread modification of gene expression in the sphingolipid rheostat and signaling pathways, which requires further research to fully understand their mechanisms of action. FINANCIAL SUPPORT: Supported by the National Science Center grant no NCN/15/B/NZ3/01049.