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.