Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation

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作者：

STEVEN W. BARGER，DOROTHEE HORSIER，KATSUTOSHI FURUKAWA，YADONG GOODMAN，JOSEF KRIEGLSTEIN，MARK P. MATTSON

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摘要：

In Alzheimer disease (AD) the amyloid β-peptide (Aβ) accumulates in plaques in the brain. Aβ can be neurotoxic by a mechanism involving induction of reactive oxygen species (ROS) and elevation of intracellular free calcium levels ([Ca2+]i). In light of evidence for an inflammatory response in the brain in AD and reports of increased levels of tumor necrosis factor (TNF) in AD brain we tested the hypothesis that TNFs affect neuronal vulnerability to Aβ. Aβ-(25-35) and Aβ-(1-40) induced neuronal degeneration in a concentration- and time-dependent manner. Pretreatment of cultures for 24 hr with TNF-β or TNF-α resulted in significant attenuation of Aβ-induced neuronal degeneration. Accumulation of peroxides induced in neurons by Aβ was significantly attenuated in TNF-pretreated cultures, and TNFs protected neurons against iron toxicity, suggesting that TNFs induce antioxidant pathways. The [Ca2+]iresponse to glutamate (quantified by fura-2 imaging) was markedly potentiated in neurons exposed to Aβ, and this action of Aβ was suppressed in cultures pretreated with TNFs. Electrophoretic mobility-shift assays demonstrated an induction of a κB-binding activity in hippocampal cells exposed to TNFs. Exposure of cultures to IκB (MAD3) antisense oligonucleotides, a manipulation designed to induce NF-κB, mimicked the protection by TNFs. These data suggest that TNFs protect hippocampal neurons against Aβ toxicity by suppressing accumulation of ROS and Ca2+and that κB-dependent transcription is sufficient to mediate these effects. A modulatory role for TNF in the neurodegenerative process in AD is proposed.

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关键词：

alzheimer disease cell death confocal laser scanning microseopy fura-2 imaging reactive oxygen species

DOI：

10.1073/pnas.92.20.9328

被引量：

751

年份：

1995