Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid- beta 1-42 peptide in mice

• Published in: Brain, behavior, and immunity behavior, and immunity, 2016-08, Vol.56, p.363-377
• Main Authors: Souza, Leandro Cattelan, Jesse, Cristiano R, Antunes, Michelle S, Ruff, Jossana Rodrigues, de Oliveira Espinosa, Dieniffer, Gomes, Nathalie Savedra, Donato, Franciele, Giacomeli, Renata, Boeira, Silvana Peterini
• Format: Article
• Language: English
• ISSN: 0889-1591
• DOI: 10.1016/j.bbi.2016.03.002

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (A beta )-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of A beta 1-42 peptide (400pmol/mice; 3 mu l/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of A beta 1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that A beta 1-42 induced memory impairment in the object recognition test. A beta 1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the A beta 1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to A beta -associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on A beta -induced neuroinflammation.