Astroglial expression of ceramide in Alzheimer's disease brains: A role during neuronal apoptosis
Astroglial expression of ceramide in Alzheimer's disease brains: A role during neuronal apoptosis
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DOI：
10.1016/j.neuroscience.2004.08.056
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发表时间：
2005-01-01
期刊：
影响因子：
3.3
通讯作者：
Okazaki, T
中科院分区：
文献类型：
--
作者：
Satoi, H;Tomimoto, H;Okazaki, T
越来越多的证据表明神经酰胺与神经退行性疾病和衰老中的细胞凋亡密切相关。我们检测了神经退行性疾病患者脑脊液或脑组织中神经酰胺的水平，以及神经细胞凋亡过程中细胞内和细胞外神经酰胺的调节机制。我们筛选了神经退行性疾病患者脑脊液中的神经酰胺水平，发现阿尔茨海默病(AD)患者的神经酰胺水平显著高于年龄匹配的肌萎缩侧索硬化症(ALS)患者和其他神经对照患者。用免疫组织化学方法检测阿尔茨海默病患者脑组织中神经酰胺在额叶皮质星形胶质细胞中的异常表达，而在ALS和正常脑组织中未检测到神经酰胺的表达。为了探讨神经酰胺在阿尔茨海默病患者脑星形胶质细胞中的调节作用，我们检测了神经酰胺在神经元凋亡过程中的代谢。在维甲酸(RA)诱导的神经细胞凋亡中，RA略微增加神经酰胺的从头合成，但有趣的是，RA显著抑制[C-14]神经酰胺向葡萄糖基神经酰胺(GlcCer)的转化，提示神经酰胺质量的增加主要是由于抑制神经酰胺代谢酶GlcCer合成酶。此外，通过追逐和转换实验发现，细胞外[C-14]鞘磷脂水平没有明显变化，培养基内[C-14]神经酰胺水平显著增加。细胞培养上清液中神经酰胺质量在RA处理48h后增加2.5倍。这些结果提示神经酰胺可能通过抑制GlcCer合成酶而调节细胞内神经酰胺的质量，并可能作为细胞外/细胞间的媒介参与神经细胞的凋亡。阿尔茨海默病患者脑脊液中神经酰胺水平的升高可能来源于星形胶质细胞，增加了AD患者对细胞间神经酰胺的反应而导致神经元凋亡的可能性。(C)2005年由爱思唯尔有限公司代表IBRO出版。
Accumulating evidences indicate that ceramide is closely involved in apoptotic cell death in neurodegenerative disorders and aging. We examined ceramide levels in the cerebrospinal fluid (CSF) or brain tissues from patients with neurodegenerative disorders and the mechanism of how intra- and extracellular ceramide was regulated during neuronal apoptosis.We screened the ceramide levels in the CSF of patients with neurodegenerative disorders, and found that ceramide was significantly increased in patients with Alzheimer's disease (AD) than in patients with age-matched amyotrophic lateral sclerosis (ALS) and other neurological controls. With immunohistochemistry in AD brains, ceramide was aberrantly expressed in astroglia in the frontal cortices, but not detected in ALS and control brains.To explore for the regulation of ceramide in astroglia in Alzheimer's disease brains, we examined the metabolism of ceramide during neuronal apoptosis. In retinoic acid (RA)induced neuronal apoptosis, RA slightly increased de novo synthesis of ceramide, but interestingly, RA dramatically inhibited conversion of [C-14] ceramide to glucosylceramide (GlcCer), suggesting that the increase of ceramide mass is mainly due to inhibition of the ceramide-metabolizing enzyme GlcCer synthase. In addition, a significant increase of the [C-14] ceramide level in the culture medium was detected by chasing and turnover experiments without alteration of extracellular [C-14] sphingomyelin levels. A 2.5-fold increase of ceramide mass in the supernatant was also detected after 48 h of treatment with RA.These results suggest a regulatory mechanism of intracellular ceramide through inhibition of GlcCer synthase and a possible role of ceramide as an extracellular/intercellular mediator for neuronal apoptosis. The increased ceramide level in the CSF from AD patients, which may be derived from astroglia, raises a possibility of neuronal apoptosis by the response to intercellular ceramide in AD. (C) 2005 Published by Elsevier Ltd on behalf of IBRO.