The role of TNF-alpha signaling pathway on COX-2 upregulation and cognitive decline induced by beta-amyloid peptide.
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.
Medeiros
Rodrigo
R
Departamento de Farmacologia, Universidade Federal de Santa Catarina, Santa Catarina, Brazil.
Figueiredo
Cláudia P
CP
Pandolfo
Pablo
P
Duarte
Filipe S
FS
Prediger
Rui D S
RD
Passos
Giselle F
GF
Calixto
João B
JB
D016229:Amyloid beta-Peptides; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009578:Nitrobenzenes / Q000494:pharmacology; D010446:Peptide Fragments; D011493:Protein Kinase C / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D016229:Amyloid beta-Peptides; D000906:Antibodies; D004791:Enzyme Inhibitors; D009578:Nitrobenzenes; D010446:Peptide Fragments; D047888:Receptors, Tumor Necrosis Factor, Type I; D013449:Sulfonamides; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C078592:amyloid beta-protein (1-40); C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D050882:CREB-Binding Protein; D011493:Protein Kinase C; D015232:Dinoprostone