161. Inhibition of indoleamine 2,3-dioxygenase prevents amyloid-beta-induced neuropsychiatric-like behaviors in mice

Abstract

Neuropsychiatric disorders, such as depression and anxiety are the most prevalent comorbidities of Alzheimer’s disease (AD), accelerating cognitive decline and impairing quality-of-life. Post-mortem analysis of brain tissue from AD patients has revealed increased proinflammatory cytokines, indicative of chronic neuroimmune activation, possibly due to AD-related pathology. Recent data has shown that activation of the immune system can precipitate neuropsychiatric symptoms, which may be mediated through the tryptophan metabolizing enzyme, indoleamine 2,3-dioxygenase (IDO). We sought to determine if central amyloid-beta (1–42) administration caused neuroimmune activation and subsequent IDO-dependent neuropsychiatric-like behaviors. Male C57BL/J6 mice received a single intracerebroventricular injection of amyloid-beta (1–42) (400 pmol/1μL) or vehicle. Sucrose preference was measured 3 days post-injection, while open field activity and behavior during the forced swim test were measured 7 days post-injections. Amyloid-beta (1–42) or vehicle was also administered to IDO deficient mice (IDO−/−) or mice pretreated with a competitive IDO inhibitor (1-methyltryptophan, 1-MT). In control mice, amyloid-beta (1–42) administration triggered an increase in depressive- and anxiety-like behaviors, characterized by a reduction in sucrose preference, decreased open field central time, increased open field thigmotaxis, and increased immobility during the forced swim test. These neuropsychiatric-like behaviors did not develop in response to amyloid-beta (1–42) administration after 1-MT pretreatment or in IDO−/− mice. Together, these data suggest IDO may play an important role in mediating AD-related neuropsychiatric disorders.