Increased brain deposition of amyloid β protein (Aβ) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-α (TNF-α)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of bothin vivoandin vitroapproaches. The intracerebroventricular injection of Aβ_1–40in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-α or iNOS reduced the cognitive deficit evoked by Aβ_1–40in mice. Similar results were obtained in TNF-α receptor 1 and iNOS knock-out mice. Aβ_1–40administration induced an increase in TNF-α expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Aβ_1–40led to activation of both JNK (c-Jun-NH₂-terminal kinase)/c-Jun and nuclear factor-κB, resulting in iNOS upregulation in both brain structures. The anti-TNF-α antibody reduced all of the molecular and biochemical alterations promoted by Aβ_1–40. These results provide new insights in mouse models of AD, revealing TNF-α and iNOS as central mediators of Aβ action. These pathways might be targeted for AD drug development.