SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling
SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling
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DOI：
10.1074/jbc.m509329200
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发表时间：
2005-12-02
影响因子：
4.8
通讯作者：
Li, G
中科院分区：
文献类型：
--
作者：
Chen, J;Zhou, YG;Li, G
越来越多的证据表明，致病蛋白诱导的神经变性依赖于周围神经胶质细胞的贡献。在这里，我们证明了小胶质细胞中的NF-κ B信号传导与淀粉样β（A β）肽诱导的神经元死亡密切相关，淀粉样β（A β）肽被广泛认为是导致阿尔茨海默病的原因。通过表达不可降解的I κ B α超阻遏物对小胶质细胞中NF-κ B信号传导的组成性抑制阻断了神经毒性，表明小胶质细胞NF-κ B信号传导在介导A β毒性中的关键作用。用A β刺激小胶质细胞增加RelA/p65在赖氨酸310处的乙酰化，其调节NF-κ B途径。过表达SIRT 1去乙酰化酶和加入SIRT 1激动剂白藜芦醇显著降低了A β刺激的NF-κ B信号传导，并具有强烈的神经保护作用。我们的研究结果支持了胶质环假说，证明了小胶质细胞NF-κ B信号在A β依赖性神经变性中的关键作用。他们还将SIRT 1与这一途径联系起来，并强调了白藜芦醇和其他sirtuin激活化合物在阿尔茨海默病中的治疗潜力。
Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-kappa B signaling in microglia is critically involved in neuronal death induced by amyloid-beta( A beta) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-kappa B signaling in microglia by expression of the nondegradable I kappa B alpha superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-kappa B signaling in mediating A beta toxicity. Stimulation of microglia with A beta increased acetylation of RelA/p65 at lysine 310, which regulates the NF-kappa B pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappa B signaling stimulated by A beta and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-kappa B signaling in A beta-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.