Despite being a proinflammatory cytokine, TNF-alpha preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF-alpha-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid beta1-42 (Abeta) resulted in the loss of CBP protein. However, this loss was compensated by TNF-alpha preconditioning as the expression of neuronal CBP was up-regulated in response to TNF-alpha treatment. The induction of CBP by TNF-alpha was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-kappaB. Interestingly, antisense knockdown of CBP abrogated the TNF-alpha-mediated preconditioning of neurons against Abeta and glutamate toxicity. Similarly in vivo, preadministration of TNF-alpha in mouse neocortex prevented Abeta-induced apoptosis and loss of choline acetyltransferase-positive cholinergic neurons. However, coadministration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF-alpha against Abeta neurotoxicity. This study illustrates a novel biological role of TNF-alpha in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.