Age-related differences in NFκB translocation and Bcl-2/Bax ratio caused by TNFα and Abeta42 promote survival in middle-age neurons and death in old neurons

Alzheimer's disease is associated with an age-related accumulation of Abeta and inflammation. The inflammatory mediator, TNF alpha activates a signaling cascade involving NF kappa B translocation to the nucleus and a beneficial or detrimental transcriptional response, depending oil the age of the neurons and the type of stress applied. Relative to treatment with Abeta42 alone, previously we found that TNF alpha 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 tat cortical neurons, neurons from old rats are killed by TNIF alpha Plus Abeta42 despite greater p50 nuclear translocation. In middle-age neurons, blocking TNFR1 does not affect NF kappa B translocation, whereas blocking TNFR2 results in an increase in NF kappa B translocation. For old neurons, blocking either receptor, does not change NF kappa B 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 NF kappa B and lower Bcl-2 levels promote death that is reduced by inhibition of either TNFR1 or R2. (C) 2008 Elsevier Inc. All rights reserved.