Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway.
Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway.
复制标题
淀粉样蛋白β肽通过激活中性鞘磷脂酶钙酰胺途径来诱导少突胶质细胞死亡。
DOI：
10.1083/jcb.200307017
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发表时间：
2004-01-05
影响因子：
7.8
通讯作者：
Hsu, Chung Y
中科院分区：
文献类型：
--
作者：
Lee, Jiunn-Tay;Xu, Jan;Lee, Jin-Moo;Ku, Grace;Han, Xianlin;Yang, Ding-I;Chen, Shawei;Hsu, Chung Y
老年斑中淀粉样β肽（Aβ）的积累是阿尔茨海默病（AD）的一个病理标志，与神经元变性有关。我们最近发现Aβ可诱导少突胶质细胞（OLG）凋亡，提示其在AD的白色病变中发挥作用。在这里，我们探讨了Aβ诱导OLG死亡的分子机制，研究了神经酰胺（一种已知的促凋亡介质）的潜在作用。Aβ和神经酰胺均可诱导OLG死亡。此外，Aβ激活中性鞘磷脂酶（nSM酶），但不激活酸性鞘磷脂酶，导致神经酰胺生成增加。用N-油酰乙醇胺阻断神经酰胺降解加剧了Aβ的细胞毒性;加入细菌鞘磷脂酶（模拟细胞nSM酶活性）诱导OLG死亡。此外，通过3-O-甲基鞘磷脂或通过使用反义寡核苷酸的基因敲除抑制nSM酶可减弱Aβ诱导的OLG死亡。谷胱甘肽（GSH）前体抑制Aβ对nSMase的激活并阻止OLG死亡，而GSH耗竭剂增加nSMase活性和Aβ诱导的死亡。这些结果表明，Aβ通过氧化机制激活nSM酶-神经酰胺级联反应诱导OLG死亡。
Amyloid-β peptide (Aβ) accumulation in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neuronal degeneration. We have recently demonstrated that Aβ induced oligodendrocyte (OLG) apoptosis, suggesting a role in white matter pathology in AD. Here, we explore the molecular mechanisms involved in Aβ-induced OLG death, examining the potential role of ceramide, a known apoptogenic mediator. Both Aβ and ceramide induced OLG death. In addition, Aβ activated neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase, resulting in increased ceramide generation. Blocking ceramide degradation with N-oleoyl-ethanolamine exacerbated Aβ cytotoxicity; and addition of bacterial sphingomyelinase (mimicking cellular nSMase activity) induced OLG death. Furthermore, nSMase inhibition by 3-O-methyl-sphingomyelin or by gene knockdown using antisense oligonucleotides attenuated Aβ-induced OLG death. Glutathione (GSH) precursors inhibited Aβ activation of nSMase and prevented OLG death, whereas GSH depletors increased nSMase activity and Aβ-induced death. These results suggest that Aβ induces OLG death by activating the nSMase–ceramide cascade via an oxidative mechanism.