Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Neurobiol Aging. 2010 Mar;31(3):398-408. doi: 10.1016/j.neurobiolaging.2008.05.010. Epub 2008 Jun 10.
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 (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta (Abeta) peptide and hyperphosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Abeta 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 Abeta-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Abeta deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis.
先前有报道称阿尔茨海默病（AD）患者的鞘脂代谢异常。为了进一步证实这些发现，我们分析了 AD 患者和年龄匹配的正常个体的脑组织样本中的几种鞘脂和鞘脂水解酶。我们发现 AD 患者中酸性鞘磷脂酶（ASM）和酸性神经酰胺酶（AC）的表达升高，导致鞘磷脂减少和神经酰胺升高。AD 大脑中还发现了更多的神经鞘氨醇，尽管神经鞘氨醇-1-磷酸（S1P）水平降低。值得注意的是，大脑 ASM 和 S1P 水平与淀粉样β肽（Abeta）和过度磷酸化的 tau 蛋白水平之间存在显著相关性。基于这些发现，我们用 Abeta 寡聚体处理神经元细胞培养物，发现 Abeta 寡聚体能激活 ASM，增加神经酰胺，并诱导细胞凋亡。用纯化的重组 AC 预先处理神经元可以防止细胞发生 Abeta 诱导的凋亡。我们提出 ASM 的激活是导致 AD 的一个重要的病理事件，可能是由于 Abeta 的沉积。ASM 激活的下游后果是神经酰胺升高、神经酰胺酶激活和神经鞘氨醇产生。AD 大脑中 S1P 水平降低，加上神经酰胺升高，可能导致疾病的发病机制。
