Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

Abstract

Sphingolipid signaling disturbances correlate with Alzheimer's disease (AD) progression. We examined the influence of FTY720/fingolimod, a sphingosine analog and sphingosine-1-phosphate (S1P) receptor modulator, on the expression of sphingolipid metabolism and signaling genes in a mouse transgenic AD model. Our results demonstrated that AβPP (V717I) transgene led with age to reduced mRNA expression of S1P receptors (S1PRs), sphingosine kinase SPHK2, ceramide kinase CERK, and the anti-apoptotic Bcl2 in the cerebral cortex and hippocampus, suggesting a pro-apoptotic shift in 12-month old mice. These changes largely emulated alterations we observed in the human sporadic AD hippocampus: reduced SPHK1, SPHK2, CERK, S1PR1, and BCL2. We observed that the responses to FTY720 treatment were modified by age and notably differed between control (APP − ) and AD transgenic (APP + ) animals. AβPP (V717I)-expressing 12-month-old animals reacted to fingolimod with wide changes in the gene expression program in cortex and hippocampus, including increased pro-survival SPHKs and CERK. Moreover, BCL2 was elevated by FTY720 in the cortex at all ages (3, 6, 12 months) while in hippocampus this increase was observed at 12 months only. In APP − mice, fingolimod did not induce any significant mRNA changes at 12 months. Our results indicate significant effect of FTY720 on the age-dependent transcription of genes involved in sphingolipid metabolism and pro-survival signaling, suggesting its neuroprotective role in AD animal model.

The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

“…Examples of up-regulated genes include the ceramide-producing synthases LASS1 , LASS2 (coding for CerS1 and CerS2, respectively) and acid sphingomyelinase ASM ; S1P lyase SGPL1 , and serine palmitoyltransferase SPTLC2 (which decides on the general ceramide/sphingolipid levels) were also increased, while the acid ceramidase ASAH1 , C1P-generating CERK , or—less obviously— LASS6 are reduced [ 76 , 77 ]. We confirmed the trend towards reduced expression of S1P- and C1P-producing enzymes ( SPHKs , CERK , S1P receptors) in human sporadic AD brains although there were slight differences in the types of genes/isoforms affected [ 271 ].…”

“…The roles of S1P in the regulation of secretion mechanisms also deserve more attention in the context of extracellular protein neurotoxicity [ 1 , 279 ]. The pattern of sphingolipid metabolic enzyme changes in AD can be largely replicated in an animal Aβ precursor protein (AβPP, V717I)-transfected model, suggesting that these alterations arise in a relatively direct way in response to high Aβ peptide production [ 271 ]. Fingolimod effects on the age-dependent transcription of survival-regulating sphingolipid metabolism genes supports the need of its in-depth characterization as a potential disease-modifying treatment in AD and other neurodegenerative disorders [ 271 ].…”

Fingolimod Affects Transcription of Genes Encoding Enzymes of Ceramide Metabolism in Animal Model of Alzheimer’s Disease

“…Aβ peptides modulate the enzymes of sphingolipid metabolism and S1P receptors in cellular models; thus, Aβ's effect appears to be relatively direct [13]. We have recently demonstrated the influence of neuronal expression of V717I AβPP on the mRNA levels of sphingosine kinases and cell surface S1P receptors [27].…”

“…Female FVB-Tg(Thy1; APP LD2/B6) mice express human AβPP harboring the "London" V717I mutation under control of thy1 promoter fragment which displays specificity towards neurons of the brain and spinal cord [27,49,50]. The model successfully recreates a relatively broad spectrum of behavioral, electrophysiological, and biochemical features of AD [49,50].…”

“…Although experimental AD models are being criticized for recreating only selected aspects of the disease with varying fidelity [26], they may be highly useful in the elucidation of molecular/biochemical events mediating the neurotoxicity of Aβ [27]. Aβ peptides modulate the enzymes of sphingolipid metabolism and S1P receptors in cellular models; thus, Aβ's effect appears to be relatively direct [13].…”