Deregulation of sphingolipid metabolism in Alzheimer's disease
Deregulation of sphingolipid metabolism in Alzheimer's disease
复制标题
DOI：
10.1016/j.neurobiolaging.2008.05.010
复制
发表时间：
2010-03-01
影响因子：
4.2
通讯作者：
Schuchman, Edward H.
中科院分区：
文献类型：
--
作者：
He, Xingxuan;Huang, Yu;Schuchman, Edward H.
先前已经报道了阿尔茨海默病（AD）中的异常鞘脂代谢。为了扩展这些发现，在AD患者和年龄匹配的正常个体的脑样本中分析了几种鞘脂和鞘脂水解酶。我们发现AD患者的酸性鞘磷脂酶（ASM）和酸性神经酰胺酶（AC）表达升高，导致鞘磷脂减少和神经酰胺升高。在AD脑中也发现了更多的鞘氨醇，尽管鞘氨醇-1-磷酸（SIP）水平降低。值得注意的是，在脑ASM和SIP水平与淀粉样蛋白β（A β）肽和过度磷酸化tau蛋白的水平之间观察到显著相关性。基于这些发现，用A β寡聚体处理神经元细胞培养物，发现A β寡聚体激活ASM，增加神经酰胺，并诱导细胞凋亡。用纯化的重组AC预处理神经元防止细胞经历A β诱导的凋亡。我们认为，ASM激活是导致AD的重要病理事件，可能是由于A β沉积。ASM激活的下游结果是神经酰胺升高、神经酰胺酶激活和鞘氨醇产生。AD脑中SIP水平的降低以及神经酰胺的升高可能有助于疾病的发病机制。(C)2008年爱思唯尔公司All rights reserved.
Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (SIP) levels were reduced. Notably, significant correlations were observed between the brain ASM and SIP levels and the levels of amyloid beta (A beta) peptide and hyperphosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with A beta oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pre-treatment of the neurons with purified, recombinant AC prevented the cells from undergoing A beta-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to A beta deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of SIP in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis. (C) 2008 Elsevier Inc. All rights reserved.