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Age‐related changes to tumor necrosis factor receptors affect neuron survival in the presence of beta‐amyloid
Author(s) -
Patel Jigisha R.,
Brewer Gregory J.
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21663
Subject(s) - tumor necrosis factor receptor 1 , neurodegeneration , tumor necrosis factor alpha , neuroprotection , receptor , neuron , biology , endocrinology , medicine , neuroscience , disease , tumor necrosis factor receptor
Inflammation including local accumulations of tumor necrosis factor alpha (TNF‐α) is a part of Alzheimer's disease pathology and may exacerbate age‐related neurodegeneration. Most studies on TNF‐α 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‐α through TNF receptor 1 (TNFR1) and receptor 2 (TNFR2) expression could increase susceptibility to β‐amyloid (1–42, Aβ42). 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 Aβ42 toxicity than middle‐aged neurons, and the addition of TNF‐α was neuroprotective in middle‐aged neurons, but exacerbated the toxicity from Aβ42 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‐α plus Aβ42 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‐α in middle‐aged neurons. However, middle‐aged neurons treated with TNF‐α plus Aβ42 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‐α surface receptor expression contribute to the neuronal loss associated with inflammation in Alzheimer's disease. © 2008 Wiley‐Liss, Inc.