Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer's disease.
Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer's disease.
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DOI：
10.1523/jneurosci.1243-10.2010
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发表时间：
2010-09-22
期刊：
影响因子：
--
通讯作者：
Pahan K
中科院分区：
文献类型：
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作者：
Jana A;Pahan K
胶质细胞活化在包括阿尔茨海默病（AD）在内的各种神经退行性疾病的发病机制中起重要作用。然而，激活的胶质细胞可以杀死神经元的分子机制知之甚少。本研究强调了中性鞘磷脂酶（N-SMase）在介导纤维状淀粉样β 1-42（Aβ1-42）肽激活的星形胶质细胞对神经元的损伤作用中的重要性。在trans-well实验中，从活化的原代人星形胶质细胞释放的可溶性产物诱导原代人神经元中中性鞘磷脂酶（N-SMase）的活化、神经酰胺的产生和细胞死亡。通过反义敲低N-SMase而非酸性鞘磷脂酶（A-SMase）保护神经元免受活化星形胶质细胞的细胞毒性作用，表明活化星形胶质细胞释放的可溶性产物通过N-SMase而非A-SMase杀死神经元。接下来，我们研究了N-SMase在人类星形胶质细胞活化中的作用。有趣的是，在Aβ1-42激活的星形胶质细胞中，通过反义寡核苷酸或化学抑制剂敲低N-SMase（而非A-SMase）可阻止促炎分子（TNF-α、iNOS、IL-1β和IL-6）的诱导和NF-κB的激活。随后，纤维状Aβ肽还诱导小鼠皮层中N-SMase和神经酰胺的激活。最重要的是，反义敲除N-SMase而不是A-SMase，降低了星形胶质细胞的活化，并保护神经元免受皮质中纤维状Aβ毒性的影响。总之，很明显，Aβ对星形胶质细胞的激活以及激活的星形胶质细胞对神经元的细胞毒性都依赖于N-SMase。
Glial activation plays an important role in the pathogenesis of various neurodegenerative disorders including Alzheimer’s disease (AD). However, molecular mechanisms by which activated glia could kill neurons are poorly understood. The present study underlines the importance of neutral sphingomyelinase (N-SMase) in mediating the damaging effect of fibrillar amyloid-β 1-42 (Aβ1-42) peptide-activated astroglia on neurons. In trans-well experiments, soluble products released from activated primary human astroglia induced the activation of neutral sphingomyelinase (N-SMase), production of ceramide and cell death in primary human neurons. Protection of neurons from cytotoxic effects of activated astroglia by antisense knockdown of N-SMase, but not acidic sphingomyelinase (A-SMase), suggests that soluble products released from activated astroglia kill neurons via N-SMase, but not A-SMase. Next we examined the role of N-SMase in the activation of human astroglia. Interestingly, knockdown of N-SMase, but not A-SMase, by either antisense oligonucleotides or chemical inhibitor prevented the induction of proinflammatory molecules (TNF-α, iNOS, IL-1β, and IL-6) and the activation of NF-κB in Aβ1-42-activated astroglia. Subsequently, fibrillar Aβ peptides also induced the activation of N-SMase and ceramide in vivo in mouse cortex. Most importantly, antisense knockdown of N-SMase, but not A-SMase, decreased the activation of astroglia and protected neurons from fibrillar Aβ toxicity in vivo in the cortex. Taken together, it is apparent that both the activation of astroglia by Aβ and that the cytotoxicity of activated astroglia on neurons depend on N-SMase.