The Molecular Mechanism of Amyloid β42 Peptide Toxicity: The Role of Sphingosine Kinase-1 and Mitochondrial Sirtuins

PloS One
Magdalena CieslikJoanna B Strosznajder

Abstract

Our study focused on the relationship between amyloid β 1-42 (Aβ), sphingosine kinases (SphKs) and mitochondrial sirtuins in regulating cell fate. SphK1 is a key enzyme involved in maintaining sphingolipid rheostat in the brain. Deregulation of the sphingolipid metabolism may play a crucial role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial function and mitochondrial deacetylases, i.e. sirtuins (Sirt3,-4,-5), are also important for cell viability. In this study, we evaluated the interaction between Aβ1-42, SphKs and Sirts in cell survival/death, and we examined several compounds to indicate possible target(s) for a strategy protecting against cytotoxicity of Aβ1-42. PC12 cells were subjected to Aβ1-42 oligomers and SphK inhibitor SKI II for 24-96 h. Our data indicated that 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 free radical formation, 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 was observed. Moreover, the total protein level of glycogen synthase kinase-3β was decreased. Aβ1...Continue Reading

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Citations

May 29, 2016·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Shun-Wang HuangShao-Jiang Song
Apr 5, 2018·Acta Neuropathologica Communications·Gaëlle DominguezMarie-Bernadette Delisle
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Mar 16, 2019·International Journal of Molecular Sciences·Ramón CacabelosDmitry Goldgaber
Nov 25, 2016·Neurochemical Research·Henryk JęśkoJoanna B Strosznajder
Jun 27, 2020·International Journal of Molecular Sciences·Héctor Albert-GascóFrancisco E Olucha-Bordonau
Nov 2, 2020·Bioorganic Chemistry·Pichjira SooknualVirapong Prachayasittikul
Dec 8, 2020·ACS Chemical Neuroscience·Keng Yoon YeongYuin Chang

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Methods Mentioned

BETA
transgenic
PCR

Software Mentioned

TotalLab4
Graph Pad
Graph Pad Prism

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