The molecular network between amyloid Beta peptide, sphingosine kinase and sirtuins in cell survival and death implication in Alzheimer's disease

• Autorzy: Strosznajder J. , Czapski G. , Cieslik M.
• Języki publikacji: EN

Abstrakty

EN

BACKGROUND AND AIMS: Deregulation of the sphingolipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Mitochondrial function and mitochondrial deacetylases, i.e. sirtuins (Sirt3,-4,-5), are also affected in AD. The aim of this study was to analyse the interaction between amyloid-β1-42 (Aβ1-42), sphingosine kinases (SphKs) and mitochondrial sirtuins in cell survival/death. METHODS: The spectrofluorometrical, immunochemical and QRT-PCR methods were applied. RESULTS: PC12 cells were subjected to Aβ1-42 oligomers and SphK inhibitor (SKI II) for 24–96 h.Aβ1-42 enhanced SphK1 expression and activity after 24 h, but down-regulated them after 96 h and had no effect on SphK2. Aβ1-42 and SKI II induced oxidative stress, disturbed the balance between pro- and anti-apoptotic proteins and evoked cell death. Simultaneously, up-regulation of anti-oxidative enzymes catalase and superoxide dismutase 2 occurred. Moreover, the total protein level of glycogen synthase kinase-3β (Gsk-3β) was reduced. Aβ1-42 significantly increased the level of mitochondrial proteins: AIF and Sirt3, -4, -5. Additional analysis demonstrated a significant role of p53 protein at very early stages of Aβ1-42 toxicity. However, during prolonged exposure to Aβ1-42, the activation of caspases, MEK/ERK, and alterations in mitochondrial permeability transition pores were also involved in mechanism responsible for cell death. Moreover, SphK product, sphingosine-1-phosphate (S1P), and Sirt activators and antioxidants, effectively prevented toxicity of Aβ1-42. CONCLUSIONS: Our data indicated that p53 protein and SphKs may be involved at early stage of molecular mechanisms of Aβ toxicity. We suggest the important role of interactions between Aβ peptide, SphKs and Sirts in pathomechanism of AD. The activation of S1P-dependent signalling and Sirts may offer a promising cytoprotective strategy. This study was supported by The National Science Centre Grant 2013/09/B/NZ3/01350 to J.B.S.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2015
• Tom: 75
• Numer: Supl.
• Opis fizyczny: p.S35

Twórcy

autor

Strosznajder J.

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

autor

Czapski G.

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

autor

Cieslik M.

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