NF-kappaB activated by ER calcium release inhibits Abeta-mediated expression of CHOP protein: enhancement by AD-linked mutant presenilin 1.
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-kappaB 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-kappaB 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 Abeta exposure, mediated both CHOP expression and NF-kappaB DNA binding activity. Further, specific inhibition of NF-kappaB resulted in greater expression of CHOP, while activation of NF-kappaB inhibited CHOP expression. The enhanced release of calcium from IP3-mediated ER stores in mPS1 neurons stimulated increased NF-kappaB compared to normal neurons, which inhibited CHOP expression. Upon blockage of NF-kappaB, exposure to Abeta caused significantly greater Abeta-mediated CHOP expression and death in mPS1 neurons compared to normal neurons. Thus, AD-linked PS1 mutations disrupt the balance between stress-induced NF-kappaB and CHOP, resulting in greater dependence on stress-induced NF-kappaB activation in mPS1 neurons.
Schapansky
Jason
J
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada.
Olson
Kelly
K
Van Der Ploeg
Randy
R
Glazner
Gordon
G
D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D053764:Presenilin-1; D051742:Transcription Factor CHOP; D002118:Calcium