TUMOR-NECROSIS-FACTOR-ALPHA AND TUMOR-NECROSIS-FACTOR-BETA PROTECT NEURONS AGAINST AMYLOID BETA-PEPTIDE TOXICITY - EVIDENCE FOR INVOLVEMENTOF A KAPPA-B-BINDING FACTOR AND ATTENUATION OF PEROXIDE AND CA2+ ACCUMULATION

In Alzheimer disease (AD) the amyloid beta-peptide (A beta) accumulate s in plaques in the brain. A beta can be neurotoxic by a mechanism inv olving induction of reactive oxygen species (ROS) and elevation of int racellular free calcium levels ([Ca2+](i)). In light of evidence for a n inflammatory response in the brain in AD and reports of increased le vels of tumor necrosis factor (TNF) in AD brain we tested the hypothes is that TNFs affect neuronal vulnerability to A beta. A beta-(25-35) a nd A beta-(1-40) induced neuronal degeneration in a concentration- and time-dependent manner. Pretreatment of cultures for 24 hr with TNF-be ta or TNF-alpha resulted in significant attenuation of AP-induced neur onal degeneration. Accumulation of peroxides induced in neurons by A b eta was significantly attenuated in TNF-pretreated cultures, and TNFs protected neurons against iron toxicity, suggesting that TNFs induce a ntioxidant pathways. The [Ca2+](i) response to glutamate (quantified b y fura-2 imaging) was markedly potentiated in neurons exposed to A bet a, and this action of A beta was suppressed in cultures pretreated wit h TNFs. Electrophoretic mobility-shift assays demonstrated an inductio n of a kappa B-binding activity in hippocampal cells exposed to TNFs. Exposure of cultures to I kappa B (MAD3) antisense oligonucleotides, a manipulation designed to induce NF-kappa B, mimicked the protection b y TNFs. These data suggest that TNFs protect hippocampal neurons again st A beta toxicity by suppressing accumulation of ROS and Ca2+ and tha t kappa B-dependent transcription is sufficient to mediate these effec ts. A modulatory role for TNF in the neurodegenerative process in AD i s proposed.