ABSTRACT
Trisomy 21 (T21) causes the condition known as Down syndrome (DS), with clear impacts on brain development and function. In a previous paper (Sullivan, 2016) we showed that T21 consistently activates the interferon (IFN) response, but the contribution of IFN hyperactivity to DS phenotypes awaits elucidation. Here, we report the results of a large plasma metabolomics study, showing that T21 disrupts tryptophan catabolism toward increased production of kynurenine (KYN) and its neurotoxic derivative quinolinic acid. We also show that stimulation of IFN signaling leads to tryptophan depletion, over-production of KYN, and super-induction of IDO1, the rate-limiting enzyme in the KYN pathway, in human cells with T21 and a mouse model of DS. Finally, cytokine profiling revealed a positive correlation between circulating levels of IFNα and KYN dysregulation in people with DS. Altogether, these results reveal a mechanism by which IFN hyperactivity could drive cognitive deficits and neurodegeneration in DS.