Salubrinal attenuates 尾-amyloid-induced neuronal death and microglial activation by inhibition of the NF-魏B pathway

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• 作者：Xiumei Huang^a ; ¹ ; ² ; Yaomin Chen^b ; ¹ ; Han Zhang^a ; ^b ; ¹ ; Qilin Ma^c ; Yun-wu Zhang^a ; ^{yunzhang@xmu.edu.cn} ; Huaxi Xu^a ; ^b ; ^{xuh@sanfordburnham.org}
• 关键词：Alzheimer's disease ; Salubrinal ; 尾-amyloid ; NF-魏B
• 刊名：Neurobiology of Aging
• 出版年：2012
• 期刊代码：202_01974580
• 类别：med
• 出版时间：May, 2012
• 卷：33
• 期：5
• 页码：1007.e9-1007.e17
• 文件大小：2055 K

摘要

Alzheimer's disease (AD) is characterized by the deposition of 尾-amyloid (A尾) peptides in the brain, inducing neuronal cell death and microglial activation. Endoplasmic reticulum (ER) stress has been proposed to be a mediator of A尾 neurotoxicity. In this study, we test whether salubrinal, an ER stress inhibitor, can protect against A尾-mediated neurotoxicity. We show in rat primary cortical neurons and mouse microglial BV-2 cells that short-term treatment with salubrinal attenuates A尾-induced neuronal death and microglial activation. Remarkably, our results show that salubrinal's neuroprotective effects are not due to inhibition of ER stress. Rather, we demonstrate that salubrinal exerts its effects through the inhibition of I魏B kinase (IKK) activation, I魏B degradation, and the subsequent nuclear factor-kappa B (NF-魏B) activation. These results elucidate inhibition of the NF-魏B pathway as a new mechanism responsible for the protective effects of salubrinal against A尾 neurotoxicity. This study also suggests that modulation of A尾-induced NF-魏B activation could be a potential therapeutic strategy for Alzheimer's disease.