The role of TNF-alpha signaling pathway on COX-2 upregulation and cognitive decline induced by beta-amyloid peptide

Behav Brain Res. 2010 May 1;209(1):165-73. doi: 10.1016/j.bbr.2010.01.040. Epub 2010 Feb 1.


Alzheimer's disease (AD), a chronic degenerative and inflammatory brain disorder characterized by neuronal dysfunction and loss, is linked to accumulation of beta-amyloid (Abeta) peptide. Tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) are proteins that have key roles in immune cell activation, inflammation and cognitive function in the brain. Here, we evaluated the link between TNF-alpha and COX-2 on the acute responses elicited by Abeta. Behavioral and molecular analyses were performed in mice after an intracerebroventricular (i.c.v.) injection of Abeta(1-40). Genetic and/or pharmacological approaches were used to inhibit TNF-alpha and COX-2. I.c.v. Abeta(1-40) injection in mice activates TNF-alpha signaling pathway resulting in COX-2 upregulation, synaptic loss and cognitive decline. Pharmacological studies revealed that COX-2 is involved in the cognitive impairment mediated by TNF-alpha. However, COX-2 inhibition failed in reducing the synaptophysin loss induced by Abeta(1-40). The COX-2 upregulation induced by Abeta(1-40) was attributed to activation of different protein kinases and transcriptional factors that are greatly regulated by TNF-alpha. Together, these results indicate that Abeta(1-40) induces the activation of several TNF-alpha-dependent intracellular signaling pathways that play a key role in the control of COX-2 upregulation and activation, synaptic loss and cognitive decline in mice. Therefore, selective TNF-alpha inhibitors may be potentially interesting tools for AD drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides*
  • Analysis of Variance
  • Animals
  • Antibodies / pharmacology
  • CREB-Binding Protein / metabolism
  • Cognition Disorders / chemically induced*
  • Cyclooxygenase 2 / metabolism*
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Electrophoretic Mobility Shift Assay / methods
  • Enzyme Inhibitors / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitrobenzenes / pharmacology
  • Peptide Fragments*
  • Protein Kinase C / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Recognition, Psychology / drug effects
  • Recognition, Psychology / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Sulfonamides / pharmacology
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*


  • Amyloid beta-Peptides
  • Antibodies
  • Enzyme Inhibitors
  • Nitrobenzenes
  • Peptide Fragments
  • Receptors, Tumor Necrosis Factor, Type I
  • Sulfonamides
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • amyloid beta-protein (1-40)
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • CREB-Binding Protein
  • Protein Kinase C
  • Dinoprostone