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

Alzheimer's disease (AD), a chronic degenerative and inflammatory brain disorder characterized by neuronal dysfunction and loss, is linked to accumulation of β-amyloid (Aβ) peptide. Tumor necrosis factor-α (TNF-α) 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-α and COX-2 on the acute responses elicited by Aβ. Behavioral and molecular analyses were performed in mice after an intracerebroventricular (i.c.v.) injection of Aβ1–40. Genetic and/or pharmacological approaches were used to inhibit TNF-α and COX-2. I.c.v. Aβ1–40 injection in mice activates TNF-α 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-α. However, COX-2 inhibition failed in reducing the synaptophysin loss induced by Aβ1–40. The COX-2 upregulation induced by Aβ1–40 was attributed to activation of different protein kinases and transcriptional factors that are greatly regulated by TNF-α. Together, these results indicate that Aβ1–40 induces the activation of several TNF-α-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-α inhibitors may be potentially interesting tools for AD drug development.