Age-related changes in TNF receptors and transcription factor translocation in response to TNFalpha and Abeta.

摘要

Inflammation including local accumulations of TNFalpha is a part of Alzheimer's disease (AD) pathology and may exacerbate age-related neurodegeneration. Most studies on TNFalpha and TNF neuronal receptors are conducted using embryonic neurons, but few studies consider age-related deficits in neurons. Age-related changes in susceptibility to TNFalpha through TNFalpha R1 and R2 expression could increase susceptibility to beta-amyloid (1-42, Abeta42). We determined how aging affects receptor expression in cultured adult rat cortical neurons. The pathologic and protective responses in old and middle-age neurons respectively correlate with higher starting TNFR1 and TNFR2 mRNA levels in old versus middle-age neurons. Middle-age neurons treated with TNFalpha plus Abeta42 do not show an increase in either R1 or R2 mRNA but old neurons show an upregulation in R2 mRNA and not R1 mRNA. Despite these mRNA changes, surface immunoreactivity of both TNFR1 and TNFR2 increase with dose of TNFalpha in middle-age neurons, but not old neurons. These findings support the hypothesis that age-related changes in TNFalpha surface receptor expression contribute to the neuronal loss associated with inflammation in AD.; TNFalpha activates a signaling cascade through NFkappaB. Transcriptional responses of NFkappaB translocation to the nucleus in neurons can be beneficial or detrimental, depending on the age of the neurons and the type and magnitude of stress applied. Here we determine the relative age-related nuclear translocation of NFkappaB by TNFalpha to promote survival of middle-age neurons or death of old neurons. Old neurons do not survive in the presence of TNFalpha plus Abeta42 despite greater nuclear translocation of the p50 subunit. 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. In the setting of old neurons, these results suggest that an overactivated translocation of NFkappaB to the nucleus promotes death that is reduced by inhibition of either TNFR1 or R2. Understanding age-related changes in NFkappaB translocation sheds light into a complex inflammatory mechanism that could provide a potential therapeutic target for the inflammatory component of Alzheimer's disease.