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

Abstract

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.

• Authors: Rodrigo Medeiros, Cláudia P Figueiredo, Pablo Pandolfo, Filipe S Duarte, Rui D S Prediger, Giselle F Passos, João B Calixto
• Journal: Behavioural brain research (Behav Brain Res) Vol. 209 Issue 1 Pg. 165-73 (May 01 2010) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 20122965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, metabolism)
• Maze Learning (drug effects, 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, physiology)
• Signal Transduction (drug effects, genetics, physiology)
• Sulfonamides (pharmacology)
• Tumor Necrosis Factor-alpha (immunology, metabolism)
• Up-Regulation (drug effects, physiology)