Chen Jennifer, Zhou Yungui, Mueller-Steiner Sarah, Chen Lin-Feng, Kwon Hakju, Yi Saili, Mucke Lennart, Gan Li
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
J Biol Chem. 2005 Dec 2;280(48):40364-74. doi: 10.1074/jbc.M509329200. Epub 2005 Sep 23.
Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-kappaB signaling in microglia is critically involved in neuronal death induced by amyloid-beta (Abeta) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-kappaB signaling in microglia by expression of the nondegradable IkappaBalpha superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-kappaB signaling in mediating Abeta toxicity. Stimulation of microglia with Abeta increased acetylation of RelA/p65 at lysine 310, which regulates the NF-kappaB pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappaB signaling stimulated by Abeta and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-kappaB signaling in Abeta-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.
越来越多的证据表明，致病性蛋白质诱导的神经退行性变依赖于周围神经胶质细胞的作用。在此，我们证明小胶质细胞中的核因子κB（NF-κB）信号通路在由淀粉样β蛋白（Aβ）肽诱导的神经元死亡中起关键作用，普遍认为Aβ肽会导致阿尔茨海默病。通过表达不可降解的IκBα超级阻遏物对小胶质细胞中的NF-κB信号通路进行组成性抑制可阻断神经毒性，表明小胶质细胞NF-κB信号通路在介导Aβ毒性中起关键作用。用Aβ刺激小胶质细胞会增加RelA/p65赖氨酸310位点的乙酰化，这会调节NF-κB通路。沉默信息调节因子2相关酶1（SIRT1）脱乙酰酶的过表达以及SIRT1激动剂白藜芦醇的添加显著降低了由Aβ刺激的NF-κB信号通路，并具有强大的神经保护作用。我们的结果通过证明小胶质细胞NF-κB信号通路在Aβ依赖性神经退行性变中的关键作用，支持了神经胶质细胞环路假说。它们还表明SIRT1参与了该通路，并突出了白藜芦醇和其他sirtuin激活化合物在阿尔茨海默病中的治疗潜力。
