Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis.
Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis.
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发表时间：
2003
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通讯作者：
L. Puglielli;Blake C. Ellis;A. Saunders;D. Kovacs
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作者：
L. Puglielli;Blake C. Ellis;A. Saunders;D. Kovacs
脂质第二信使神经酰胺调节衰老过程中发生的几个生化事件。此外，它的水平在阿尔茨海默病患者的淀粉样蛋白负荷的大脑中高度升高。在这里，我们分析了异常的神经酰胺水平对淀粉样β肽（Abeta）的产生的影响，通过使用神经酰胺，C6-神经酰胺的细胞可渗透的类似物，和鞘磷脂/鞘糖脂生物合成途径的几种生化抑制剂。我们发现，C6-神经酰胺通过影响淀粉样前体蛋白的β-切割而不是γ-切割来增加Abeta的生物合成。与C6-神经酰胺类似，中性鞘磷脂酶处理诱导的内源性神经酰胺水平增加也促进了Abeta的生物合成。相反，伏马菌素B1，抑制内源性神经酰胺的生物合成，减少Abeta的生产。外源性C6-神经酰胺恢复伏马菌素B1处理的细胞内神经酰胺水平和Abeta生成。这些事件是淀粉样前体蛋白特异性的，与凋亡细胞死亡无关。脉冲追踪和时间过程降解实验表明，神经酰胺后分解稳定β-分泌酶BACE 1。总之，这些数据表明，在阿尔茨海默病患者的大脑中升高的脂质第二信使神经酰胺增加了BACE 1的半衰期，从而促进了Abeta生物合成。
The lipid second messenger ceramide regulates several biochemical events that occur during aging. In addition, its level is highly elevated in the amyloid-burdened brains of Alzheimer's disease patients. Here, we analyzed the impact of aberrant ceramide levels on amyloid beta-peptide (Abeta) generation by using a cell-permeable analog of ceramide, C6-ceramide, and several biochemical inhibitors of the sphingomyelin/glycosphingolipid biosynthetic pathway. We found that C6-ceramide increased the biogenesis of Abeta by affecting beta-but not gamma-cleavage of the amyloid precursor protein. Similarly to C6-ceramide, increased levels of endogenous ceramide induced by neutral sphingomyelinase treatment also promoted the biogenesis of Abeta. Conversely, fumonisin B1, which inhibits the biosynthesis of endogenous ceramide, reduced Abeta production. Exogenous C6-ceramide restored both intracellular ceramide levels and Abeta generation in fumonisin B1-treated cells. These events were specific for amyloid precursor protein and were not associated with apoptotic cell death. Pulse-chase and time-course degradation experiments showed that ceramide post-translationally stabilizes the beta-secretase BACE1. Taken together, these data indicate that the lipid second messenger ceramide, which is elevated in the brains of Alzheimer's disease patients, increases the half-life of BACE1 and thereby promotes Abeta biogenesis.