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Fingolimod Affects Transcription of Genes Encoding Enzymes of Ceramide Metabolism in Animal Model of Alzheimer's Disease.
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2020-04-30 , DOI: 10.1007/s12035-020-01908-3
Henryk Jęśko 1 , Przemysław L Wencel 2 , Sylwia Wójtowicz 1 , Joanna Strosznajder 1 , Walter J Lukiw 3, 4, 5 , Robert P Strosznajder 2
Affiliation  

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.

中文翻译:

芬戈莫德影响阿尔茨海默氏病动物模型中神经酰胺代谢酶编码基因的转录。

鞘脂信号的失衡可能与阿尔茨海默氏病(AD)的神经变性级联反应中的上游事件密切相关。我们分析了突变(V717I)淀粉样β前体蛋白(AβPP)转基因对小鼠海马鞘脂代谢酶的影响。在3个月大时,AβPP/Aβ的存在会上调挽救途径中的神经酰胺转换酶:神经酰胺合酶(CERS2,CERS4,CERS6)以及神经酰胺酶ACER3。在6个月时,仅CERS6升高,而在12个月时神经酰胺合酶没有增加。但是,在鞘磷脂酶途径上利用神经酰胺的鞘磷脂合酶有所减少(SGMS1在12个月,SGMS2在6个月)。与年龄匹配的对照组相比,鞘氨醇合成酶SGMS1和SGMS2的mRNA在人AD海马和新皮层中也显着下调。我们的发现表明,鞘脂稳态的早期失调有利于神经酰胺信号传导。芬戈莫德(FTY720)是一种鞘氨醇1-磷酸受体的调节剂,可在3个月后抵抗海马神经酰胺合酶CERS2的AβPP依赖性上调。此外,在12个月时,FTY720增加了神经酰胺-神经鞘氨醇更新的酶:CERS4,ASAH1和ACER3。我们还观察到芬戈莫德对鞘磷脂酶途径酶表达的影响。FTY720抵消了鞘磷脂合成酶SGMS1 / 2的AβPP连锁减少(分别在12和6个月时),并导致鞘磷脂酶SMPD2升高(在6和12个月时)。因此,
更新日期:2020-04-30
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