Age-related changes to tumor necrosis factor receptors affect neuron survival in the presence of beta-amyloid.
Inflammation including local accumulations of tumor necrosis factor alpha (TNF-alpha) is a part of Alzheimer's disease pathology and may exacerbate age-related neurodegeneration. Most studies on TNF-alpha and TNF neuronal receptors are conducted by using embryonic neurons. Few studies consider age-related deficits that may occur in neurons. Age-related changes in susceptibility to TNF-alpha through TNF receptor 1 (TNFR1) and receptor 2 (TNFR2) expression could increase susceptibility to beta-amyloid (1-42, Abeta42). Evidence is conflicting about which receptor mediates survival and/or apoptosis. We determined how aging affects receptor expression in cultured adult rat cortical neurons. Old neurons were more susceptible to Abeta42 toxicity than middle-aged neurons, and the addition of TNF-alpha was neuroprotective in middle-aged neurons, but exacerbated the toxicity from Abeta42 in old neurons. These pathologic and protective responses in old and middle-aged neurons, respectively, correlated with higher starting TNFR1 and TNFR2 mRNA levels in old vs. middle-aged neurons. Middle-aged neurons treated with TNF-alpha plus Abeta42 did not show an increase in either TNFR1 or TNFR2 mRNA, but old neurons showed an up-regulation in TNFR2 mRNA and not TNFR1 mRNA. Despite these mRNA changes, surface immunoreactivity of both TNFR1 and TNFR2 increased with the dose of TNF-alpha in middle-aged neurons. However, middle-aged neurons treated with TNF-alpha plus Abeta42 showed an up-regulation in both TNFR1 and TNFR2 surface expression, whereas old neurons failed to up-regulate surface expression of either receptor. These findings support the hypothesis that age-related changes in TNF-alpha surface receptor expression contribute to the neuronal loss associated with inflammation in Alzheimer's disease.
Patel
Jigisha R
JR
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University, School of Medicine, Springfield, Illinois 62702, USA.
Brewer
Gregory J
GJ
D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D015870:Gene Expression; D008297:Male; D009474:Neurons / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor