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

Ramendra N. Saha, Anamitra Ghosh, Carlos A. Palencia, Yiu K. Fung, Serena M. Dudek, Kalipada Pahan

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2068-2078
Number of pages11
JournalJournal of Immunology
Issue number3
StatePublished - Aug 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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