Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice

Abstract

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 (Aβ)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (400pmol/mice; 3μl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aβ1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aβ1-42 induced memory impairment in the object recognition test. Aβ1-42 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 Aβ1-42-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 Aβ-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 Aβ-induced neuroinflammation.

Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model

“…Our results also showed that 1-MT-treated BDL rats had restored memory performance and learned faster than non-treated rats, suggesting IDO regulation may be related to the memory deficits induced by BDL surgery. Corroborating our results, 1-MT treatment can ameliorate the memory deficit induced by amyloid-β1-42 peptide in mice [ 54 ].…”

“…Some earlier researches confirmed our results: BDL rats spent less time in the open arms and more time in the closed arms of the maze as compared to the control animals [ 52 , 53 ]. Furthermore, Souza et al’s study had shown that 1-MT may process anti-anxiety-like action in neurodegenerative disorder [ 54 ].…”

Lupeol, a Plant-Derived Triterpenoid, Protects Mice Brains against Aβ-Induced Oxidative Stress and Neurodegeneration

“…In the present study, we investigated the neuroprotective mechanism of lupeol in the Aβ-mouse model of AD, which suggested that lupeol suppressed the elevated oxidative stress, neuroinflammation, and memory and cognitive dysfunctions. The pathogenesis of AD occurred due to the accumulation of toxic Aβ-peptide in the central nervous system, causing synaptic dysfunction, neuronal cell death, and memory and cognitive impairments [ 42 , 43 ]. The amyloid precursor protein (APP) can be cleaved by the beta-amyloid cleaving enzyme (BACE-1), which accelerates the production of Aβ-peptide in the brain.…”

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

“…KP is unbalanced in some neurodegenerative disorders and, as a result, Trp catabolism leads to neurotoxic metabolites such as 3-hydroxykunurenine. IDO1 is essential for this pathway, and its activation has been linked with A β -related inflammation in AD [ 49 ], making it the focus of various researches on neurodegenerative diseases treatment [ 50 – 51 ]. Lu et al have identified a novel structure endowed with double activity on BuChE and IDO1 [ 52 ].…”