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, TNFα activates a signaling cascade involving NFκB 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 TNFα 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 TNFα plus Abeta42 despite greater p50 nuclear translocation. In middle-age neurons, blocking TNFR1 does not affect NFκB translocation, whereas blocking TNFR2 results in an increase in NFκB translocation. For old neurons, blocking either receptor, does not change NFκB 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 NFκB and lower Bcl-2 levels promote death that is reduced by inhibition of either TNFR1 or R2.