Salubrinal attenuates β-amyloid-induced neuronal death and microglial activation by inhibition of the NF-κB pathway

Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid (A beta) peptides in the brain, inducing neuronal cell death and microglial activation. Endoplasmic reticulum (ER) stress has been proposed to be a mediator of A beta neurotoxicity. In this study, we test whether salubrinal, an ER stress inhibitor, can protect against A beta-mediated neurotoxicity. We show in rat primary cortical neurons and mouse microglial BV-2 cells that short-term treatment with salubrinal attenuates A beta-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 kappa B kinase (IKK) activation, I kappa B degradation, and the subsequent nuclear factor-kappa B (NF-kappa B) activation. These results elucidate inhibition of the NF-kappa B pathway as a new mechanism responsible for the protective effects of salubrinal against A beta neurotoxicity. This study also suggests that modulation of A beta-induced NF-kappa B activation could be a potential therapeutic strategy for Alzheimer's disease. (C) 2012 Elsevier Inc. All rights reserved.