NF-κB activated by ER calcium release inhibits Aβ-mediated expression of CHOP protein: Enhancement by AD-linked mutant presenilin 1

Abstract Mutations in presenilin which result in early-onset Alzheimer disease (AD) cause both increased calcium release from intracellular stores, primarily endoplasmic reticulum (ER), and changes in NF-κB activation. Some studies have also reported that neurons containing AD-linked mutant presenilins (mPS1) show increased vulnerability to various stresses, while others report no differences in neuronal death. The majority of these reports center on potential changes in ER stress, because of the enhanced ER calcium release seen in mPS1 neurons. One of the primary death effectors of ER stress is CHOP, also termed GADD153, which acts to transcriptionally inhibit protective cellular molecules such as Bcl-2 and glutathione. Because both CHOP and NF-κB are activated by increased intracellular calcium and stress, yet have diametrically opposite effects on neuronal vulnerability, we sought to examine this interaction in greater detail. We observed that IP3-mediated calcium release from ER, stimulated by Aβ exposure, mediated both CHOP expression and NF-κB DNA binding activity. Further, specific inhibition of NF-κB resulted in greater expression of CHOP, while activation of NF-κB inhibited CHOP expression. The enhanced release of calcium from IP3-mediated ER stores in mPS1 neurons stimulated increased NF-κB compared to normal neurons, which inhibited CHOP expression. Upon blockage of NF-κB, exposure to Aβ caused significantly greater Aβ-mediated CHOP expression and death in mPS1 neurons compared to normal neurons. Thus, AD-linked PS1 mutations disrupt the balance between stress-induced NF-κB and CHOP, resulting in greater dependence on stress-induced NF-κB activation in mPS1 neurons.