Up-regulation of the brain indoleamine 2,3-dioxygenase activity in a mouse model of Alzheimer's disease by systemic endotoxin challenge

.Inflammation is suspected to be a critical component of the progression and severity of neurodegeneration in Alzheimer's disease (AD). The kynurenine pathway (KP), which is the major route for tryptophan degradation, is activated in central nervous system (CNS) inflammation. The activation of KP, which is caused by the up-regulation of indoleamine 2,3-dioxygenase (IDO), leads to the production of some neurotoxic metabolites (e.g., quinolinic acid). To address the hypothesis that the KP may play a role in the pathogenesis of the AD brain, we examined the IDO activity in the brain of the Tg2576 transgenic mouse model of AD. The IDO activity was detected in the brain of the mouse model of AD, but the level was not significantly different from that of the age-matched nontransgenic control mice. In contrast, when CNS inflammation was induced in this mouse model by a single intraperitoneal injection of lipopolysaccharide (LPS), a marked (3-fold) increase in the IDO activity was observed, but not in the control mice with the same treatment. These results suggest that peripheral inflammation activates the CNS KP in the AD brain, leading to the production of neurotoxic metabolites and thereby inducing neuronal death.