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

Abstract

The imbalance in sphingolipid signaling may be critically linked to the upstream events in the neurodegenerative cascade of Alzheimer's disease (AD). We analyzed the influence of mutant (V717I) amyloid β precursor protein (AβPP) transgene on sphingolipid metabolism enzymes in mouse hippocampus. At 3 months of age AβPP/Aβ presence upregulated enzymes of ceramide turnover on the salvage pathway: ceramide synthases (CERS2, CERS4, CERS6) and also ceramidase ACER3. At 6 months, only CERS6 was elevated, and no ceramide synthase was increased at 12 months. However, sphingomyelin synthases, which utilize ceramide on the sphingomyelinase pathway, were reduced (SGMS1 at 12 and SGMS2 at 6 months). mRNAs for sphingomyelin synthases SGMS1 and SGMS2 were also significantly downregulated in human AD hippocampus and neocortex when compared with age-matched controls. Our findings suggest early-phase deregulation of sphingolipid homeostasis in favor of ceramide signaling. Fingolimod (FTY720), a modulator of sphingosine-1-phosphate receptors countered the AβPP-dependent upregulation of hippocampal ceramide synthase CERS2 at 3 months. Moreover, at 12 months, FTY720 increased enzymes of ceramide-sphingosine turnover: CERS4, ASAH1, and ACER3. We also observed influence of fingolimod on the expression of the sphingomyelinase pathway enzymes. FTY720 counteracted the AβPP-linked reduction of sphingomyelin synthases SGMS1/2 (at 12 and 6 months, respectively) and led to elevation of sphingomyelinase SMPD2 (at 6 and 12 months). Therefore, our results demonstrate potentially beneficial, age-specific effects of fingolimod on transcription of sphingolipid metabolism enzymes in an animal model of AD.

Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target

“…Because sphingomyelin and sphingolipid signaling activate the pro-survival S1P-S1P receptor pathway [ 23 ], we next investigated if sphingomyelin and S1P synthesis in acid-induced OS spheroids was able to modulate cell viability. To this aim, we used myriocin, an inhibitor of serine palmitoyltransferase (SPT) [ 52 ], and its derivative FTY720 (Fingolimod), which inhibits G protein-coupled S1P receptors and blocks oncogenic signaling [ 53 , 54 , 55 , 56 ]. Both myriocin and FTY720 were able to impair S1P accumulation in 143B spheroids under acidity, with a greater effect shown by FTY720 ( Figure 3 E).…”

“…FTY720 has several anticancer effects [ 77 , 78 , 79 , 80 , 81 ] but its activity in OS has not been explored so far. Despite being considered an S1P receptor modulator, FTY720 is also able to induce changes in the enzymes of the sphingolipid pathway, including SPHK1 [ 54 , 55 , 56 ], thus providing an explanation for the reduction of S1P seen in our model. FTY720 inhibited LD and S1P accumulation in acid-treated spheroids, and, as a consequence, impaired cell survival and migration.…”

Age-Related Transcriptional Deregulation of Genes Coding Synaptic Proteins in Alzheimer's Disease Murine Model: Potential Neuroprotective Effect of Fingolimod

“…The mutation is linked to familial FAD/early onset AD and stimulates the production of Aβ, especially its most toxic 42 amino acid species. Despite obvious limitations shared with other animal models of AD, the mice display a temporal sequence of behavioral alterations characteristic for AD and relatively closely follow disturbances of sphingolipid metabolism we noted in the human brain (Moechars et al, 1999;Van Dorpe et al, 2000;Jeśko et al, 2019bJeśko et al, , 2020.…”

“…Our previous analysis (Jeśko et al, 2019b(Jeśko et al, , 2020 has shown that the reaction of mouse brain to the expression of AβPP (V717I) transgene is highly different at various ages. The presence of AβPP in adult (3-month-old) animals was associated with elevated ceramide turnover (higher expression of both ceramide-synthesizing and -degrading enzymes of the salvage pathway of sphingolipid metabolism), but 12-month-old transgenic mice only displayed a reduction in the expression of ceramide-utilizing enzymes in the sphingomyelinase pathway.…”

“…The cell membrane receptors for S1P (S1PR1−5) bind to G 12 / 13 , G q , and G i proteins, and are able to influence transcription factors, such as AP-1, NF-kB, p53, or the splicing regulator SRSF1 (Kaneider et al, 2004;Van Brocklyn and Williams, 2012;Patwardhan et al, 2014;Czubowicz et al, 2019;Jeśko et al, 2019a). Strikingly, Aβ is able to modify the expression of sphingolipid-related genes (Kaneider et al, 2004;Jeśko et al, 2019bJeśko et al, , 2020. This may explain the above-mentioned shift from S1P signaling toward ceramide production, which is observed in the brain in the early stages of AD and preceding mild cognitive impairment (MCI) (Katsel et al, 2007;Han, 2010;Couttas et al, 2014).…”