Alzheimer’s disease (AD) induces time-dependent changes in sphingolipid metabolism, which may affect transcription regulation and neuronal phenotype. We therefore analyzed the influence of age, amyloid  precursor protein (APP) and the clinically approved, bioavailable sphingosine-1-phosphate receptor modulator FTY720 on the expression of synaptic proteins. RNA was isolated, reverse-transcribed, and subjected to real-time PCR. Expression of mutant (V717I) APP led to few changes at 3 months of age, but reduced multiple mRNAs coding for synaptic proteins in 12 months old mouse brain. Complexin (Cplx1), SNAP25 (Snap25), syntaxin (Stx1a), neurexin (Nrxn1), neurofilament light (Nefl) and synaptotagmin (Syt1) in the hippocampus, and VAMP1 (Vamp1) and neurexin (Nrxn1) in the cortex were all significantly reduced in 12 month old mice. Postmortem AD samples from human hippocampus and cortex displayed lower expression of VAMP, synapsin, neurofilament light (NF-L) and synaptophysin. The potentially neuroprotective FTY720 reversed most APP-induced changes in gene expression (complexin, syntaxin, SNAP25, neurexin) in 12 month old hippocampus, which is thought to be the most sensitive to early neurotoxic insults, but it only restored Vamp1 in the cortex and had no influence in 3 months old brains. Further work may reveal the potential usefulness of FTY720 in the modulation of deregulated neuronal phenotype in AD brains.

中文翻译：

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阿尔茨海默病小鼠模型中编码突触蛋白的基因与年龄相关的转录失调。芬戈莫德的潜在神经保护作用。


阿尔茨海默病 (AD) 会诱导鞘脂代谢发生时间依赖性变化，这可能会影响转录调节和神经元表型。因此，我们分析了年龄、淀粉样蛋白  前体蛋白 (APP) 和临床批准的生物可利用的 1-磷酸鞘氨醇受体调节剂 FTY720 对突触蛋白表达的影响。分离 RNA、逆转录并进行实时 PCR。突变体 (V717I) APP 的表达在 3 个月大的小鼠大脑中几乎没有变化，但减少了 12 个月大的小鼠大脑中编码突触蛋白的多个 mRNA。海马中的复合蛋白（Cplx1）、SNAP25（Snap25）、突触蛋白（Stx1a）、神经毒素（Nrxn1）、神经丝光（Nefl）和突触结合蛋白（Syt1）以及皮质中的VAMP1（Vamp1）和神经毒素（Nrxn1）均显着升高。 12个月大的小鼠中减少。来自人类海马体和皮质的死后 AD 样本显示 VAMP、突触蛋白、神经丝光 (NF-L) 和突触素的表达较低。潜在的神经保护作用 FTY720 逆转了 12 个月大海马体中 APP 诱导的大部分基因表达变化（复合蛋白、突触蛋白、SNAP25、神经毒素），海马体被认为对早期神经毒性损伤最敏感，但它仅恢复了 12 个月大海马体中的 Vamp1。皮层，对 3 个月大的大脑没有影响。进一步的工作可能会揭示 FTY720 在调节 AD 大脑中失调的神经元表型方面的潜在用途。