Abstract：
BACKGROUND: The plasma ceramide levels in Alzheimer\'s disease (AD) patients are found abnormally elevated, which is related to cognitive decline.
OBJECTIVE: This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD.
RESULTS: The ICR mice intracerebroventricularly injected with Aβ1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData.
CONCLUSIONS: Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis.
OBJECTIVE: This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD.
RESULTS: The ICR mice intracerebroventricularly injected with Aβ1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData.
CONCLUSIONS: Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis.
摘要：
背景：发现阿尔茨海默病（AD）患者的血浆神经酰胺水平异常升高，这与认知能力下降有关。
目的：本研究旨在探讨神经酰胺异常升高在AD发病中的作用机制。
结果:以Aβ1-42脑室内注射的ICR小鼠和APP/PS1转基因小鼠作为AD小鼠。认知缺陷，观察到情景和空间记忆受损，而自发能力没有改变。血清p-tau和神经酰胺水平明显升高。糖原合成酶激酶-3β(GSK-3β)和蛋白磷酸酶2A(PP2A)的表达和活性改变影响血清p-tau含量。AD小鼠肝脏中神经酰胺合成相关基因sptlc1、sptlc2、cers2、cers6水平升高,而神经酰胺降解相关基因asah2没有显著变化。这些基因的调控是通过激活的核因子κB（NF-κB）信号传导进行的。NF-κB,由游离脂肪酸(FFA)促进，也增加了肝脏中促炎细胞因子的浓度。FFA量受脂肪酸合成相关基因acc1和srepp-1c调节。此外,在下丘脑中发现前体黑皮质素（pomc）mRNA水平降低，而黑皮皮质素受体4（MC4R）mRNA水平升高。生物信息学分析证明了使用GEO数据集和AlzData的结果。
结论：神经酰胺与p-tau升高和认知功能受损呈正相关。下丘脑神经酰胺和内质网应激的增加与脂肪酸合成和通过脑-肝轴的NF-κB信号呈正相关。
目的：本研究旨在探讨神经酰胺异常升高在AD发病中的作用机制。
结果:以Aβ1-42脑室内注射的ICR小鼠和APP/PS1转基因小鼠作为AD小鼠。认知缺陷，观察到情景和空间记忆受损，而自发能力没有改变。血清p-tau和神经酰胺水平明显升高。糖原合成酶激酶-3β(GSK-3β)和蛋白磷酸酶2A(PP2A)的表达和活性改变影响血清p-tau含量。AD小鼠肝脏中神经酰胺合成相关基因sptlc1、sptlc2、cers2、cers6水平升高,而神经酰胺降解相关基因asah2没有显著变化。这些基因的调控是通过激活的核因子κB（NF-κB）信号传导进行的。NF-κB,由游离脂肪酸(FFA)促进，也增加了肝脏中促炎细胞因子的浓度。FFA量受脂肪酸合成相关基因acc1和srepp-1c调节。此外,在下丘脑中发现前体黑皮质素（pomc）mRNA水平降低，而黑皮皮质素受体4（MC4R）mRNA水平升高。生物信息学分析证明了使用GEO数据集和AlzData的结果。
结论：神经酰胺与p-tau升高和认知功能受损呈正相关。下丘脑神经酰胺和内质网应激的增加与脂肪酸合成和通过脑-肝轴的NF-κB信号呈正相关。
