Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer's Disease.
Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer's Disease.
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DOI：
10.1007/s12035-018-1040-x
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发表时间：
2019-01
影响因子：
5.1
通讯作者：
Strosznajder RP
中科院分区：
文献类型：
--
作者：
Jęśko H;Wencel PL;Lukiw WJ;Strosznajder RP
鞘脂信号传导紊乱与阿尔茨海默病 (AD) 进展相关。我们研究了 FTY720/芬戈莫德（一种鞘氨醇类似物和 1-磷酸鞘氨醇 (S1P) 受体调节剂）对小鼠转基因 AD 模型中鞘脂代谢和信号基因表达的影响。我们的结果表明，随着年龄的增长，AβPP (V717I) 转基因导致大脑皮层和海马中 S1P 受体 (S1PR)、鞘氨醇激酶 SPHK2、神经酰胺激酶 CERK 以及抗凋亡 Bcl2 的 mRNA 表达减少，表明 12 个月大的小鼠出现促凋亡转变。这些变化很大程度上模仿了我们在人类散发性 AD 海马体中观察到的变化：SPHK1、SPHK2、CERK、S1PR1 和 BCL2 减少。我们观察到，对 FTY720 治疗的反应因年龄而改变，并且对照 (APP-) 和 AD 转基因 (APP+) 动物之间存在显着差异。表达 AβPP (V717I) 的 12 个月大动物对芬戈莫德产生反应，皮质和海马的基因表达程序发生广泛变化，包括促生存 SPHK 和 CERK 增加。此外，FTY720 在所有年龄段（3、6、12 个月）的皮层中 BCL2 均升高，而在海马体中，仅在 12 个月时观察到这种升高。在 APP− 小鼠中，芬戈莫德在 12 个月时没有引起任何显着的 mRNA 变化。我们的结果表明，FTY720 对参与鞘脂代谢和促生存信号传导的基因的年龄依赖性转录具有显着影响，表明其在 AD 动物模型中具有神经保护作用。
Sphingolipid signaling disturbances correlate with Alzheimer’s disease (AD) progression. We examined the influence of FTY720/fingolimod, a sphingosine analog and sphingosine-1-phosphate (S1P) receptor modulator, on the expression of sphingolipid metabolism and signaling genes in a mouse transgenic AD model. Our results demonstrated that AβPP (V717I) transgene led with age to reduced mRNA expression of S1P receptors (S1PRs), sphingosine kinase SPHK2, ceramide kinase CERK, and the anti-apoptotic Bcl2 in the cerebral cortex and hippocampus, suggesting a pro-apoptotic shift in 12-month old mice. These changes largely emulated alterations we observed in the human sporadic AD hippocampus: reduced SPHK1, SPHK2, CERK, S1PR1, and BCL2. We observed that the responses to FTY720 treatment were modified by age and notably differed between control (APP−) and AD transgenic (APP+) animals. AβPP (V717I)-expressing 12-month-old animals reacted to fingolimod with wide changes in the gene expression program in cortex and hippocampus, including increased pro-survival SPHKs and CERK. Moreover, BCL2 was elevated by FTY720 in the cortex at all ages (3, 6, 12 months) while in hippocampus this increase was observed at 12 months only. In APP− mice, fingolimod did not induce any significant mRNA changes at 12 months. Our results indicate significant effect of FTY720 on the age-dependent transcription of genes involved in sphingolipid metabolism and pro-survival signaling, suggesting its neuroprotective role in AD animal model.
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影响因子：
7.1
作者：
Couttas TA;Kain N;Daniels B;Lim XY;Shepherd C;Kril J;Pickford R;Li H;Garner B;Don AS
通讯作者：
Don AS
影响因子：
3.7
作者：
Arana, Lide;Gangoiti, Patricia;Gomez-Munoz, Antonio
通讯作者：
Gomez-Munoz, Antonio
影响因子：
3.5
作者：
Gangoiti, Patricia;Granado, Maria H.;Gomez-Munoz, Antonio
通讯作者：
Gomez-Munoz, Antonio
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
2.7
作者：
Fukumoto, Kazuya;Mizoguchi, Hiroyuki;Suzumura, Akio
通讯作者：
Suzumura, Akio