TNF-α preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein

Despite being a proinflammatory cytokine, TNF-α 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-α-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid β1-42 (Aβ) resulted in the loss of CBP protein. However, this loss was compensated by TNF-α reconditioning as the expression of neuronal CBP was up-regulated in response to TNF-α treatment. The induction of CBP by TNF-α was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-κB. Interestingly, antisense knockdown of CBP abrogated the TNF-α-mediated preconditioning of neurons against Aβ and glutamate toxicity. Similarly in vivo, preadministration of TNF-α in mouse neocortex prevented Aβ-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-α gainst Aβ neurotoxicity. This study illustrates a novel biological role of TNF-α in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.