Fingolimod (FTY720 - modulator of sphingosine 1-phosphate receptors) alters genes expression of selected NADplus-dependent enzymes in an animal model of Alzheimer’s disease

• Autorzy: Wencel P. , Jesko H. , Strosznajder R.P.
• Języki publikacji: EN

Abstrakty

EN

INTRODUCTION: Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) belong to the family of NAD+ ‑dependent enzymes. Both are involved in the regulation of energy homeostasis, cellular stress response, and DNA repair. Recent data suggest that alterations of bioactive sphingolipids level as well as SIRTs and PARPs may be involved in Alzheimer’s disease (AD) pathology, finally leading to the progression of disease. AIM(S): In this study, the effect of FTY720 administration on mRNA levels of SIRTs and PARP‑1 in an animal model of AD was examined. METHOD(S): 3‑, 6‑, and 12‑month‑old (3M, 6M, 12M) FVB/APP+ transgenic mice with London APP (V717I) mutation were used in this study. Mice without the mutation (APP- ) were used as the control. Animals received i.p. FTY720 (1mg/kg b.w.) or NaCl (vehicle) for 2 weeks. Brain cortex was isolated and qPCR methods were applied. RESULTS: A significant downregulation of Sirt1 mRNA levels in the cortex of 3M APP+ mice vs. APP- was observed. We also observed a tendency for a reduction of 6M Sirt3 and Sirt4 mRNA levels in APP+ mice. Administration of FTY720 increased mRNA levels of Sirt1 in 3M APP+ mice as well as Parp1, Sirt1, 3, 5 in 6M APP+ mice compared to APP+ mice treated with vehicle. Moreover, FTY720 elevated Parp1, Sirt1, and Sirt3 mRNA levels in 12M APP+ mice. CONCLUSIONS: The results of our study revealed a potential link between bioactive sphingolipids and NAD+ ‑dependent enzymes. These results may also indicate an FTY720-modulatory role in SIRTs and PARPs gene expression and may offer a useful tool in the therapeutic strategy of neurodegenerative disorders. FTY720, through the activation of mitochondrial sirtuins (Sirt3,5), may improve anti-oxidative defense and protect cells against oxidative stress evoked by amyloid beta toxicity. Moreover, through activation of Sirt1 and Parp1 gene expression, FTY720 may enhance DNA repair processes. FINANCIAL SUPPORT: Supported by the National Science Centre grant no. NCN 2014/15/B/NZ3/01049 and Mossakowski MRC PAS statutory theme no.7.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2019
• Tom: 79
• Numer: Suppl.1
• Opis fizyczny: p.LXXX-LXXXI

Twórcy

autor

Wencel P.

• Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Jesko H.

• Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Strosznajder R.P.

• Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland