title: Age-related differences in NFkappaB translocation and Bcl-2/Bax ratio caused by TNFalpha and Abeta42 promote survival in middle-age neurons and death in old neurons.
abstract: Alzheimer's disease is associated with an age-related accumulation of Abeta and inflammation. The inflammatory mediator, TNFalpha activates a signaling cascade involving NFkappaB translocation to the nucleus and a beneficial or detrimental transcriptional response, depending on the age of the neurons and the type of stress applied. Relative to treatment with Abeta42 alone, previously we found that TNFalpha plus Abeta42, applied to old rat neurons (24 month) is toxic, while the same treatment of middle-age neurons (10 month) is protective. In contrast to improved survival of middle-age rat cortical neurons, neurons from old rats are killed by TNFalpha plus Abeta42 despite greater p50 nuclear translocation. In middle-age neurons, blocking TNFR1 does not affect NFkappaB translocation, whereas blocking TNFR2 results in an increase in NFkappaB translocation. For old neurons, blocking either receptor, does not change NFkappaB translocation, but improves cell survival. To account for these effects on cell viability in response to TNF+Abeta, measures of the Bcl-2/Bax ratio positively correlate with survival. In the setting of old neurons, these results suggest that overactivated nuclear translocation of NFkappaB and lower Bcl-2 levels promote death that is reduced by inhibition of either TNFR1 or R2.
authors.affiliation: Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University, School of Medicine, Springfield, IL, USA.
authors.forename: Jigisha R
authors.initials: JR
authors.lastname: Patel
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Brewer
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000633:toxicity; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D051028:bcl-2-Associated X Protein