Estrogen regulates cognitive function in APP/PS1 female mice via modulation of IDO1-mediated Trp/Kyn metabolism through ERβ.

Alzheimer's disease (AD) is more prevalent in postmenopausal women, possibly due to estrogen deficiency. IDO1 (Indoleamine 2,3-dioxygenase 1), a tryptophan-metabolizing enzyme, mediates immunomodulation and neuroinflammation and may be related to cognitive impairment in AD. This study used APP/PS1 transgenic female mice with ovariectomy (OVX),E2, IDO1 inhibitor (1-MT), and agonists and antagonists of estrogen receptors to explore the potential roles of estrogen and IDO1 in AD. Results showed that OVX aggravated the cognitive function impairment of the APP/PS1 mice. OVX also decreased the serum E2 level and increased the hippocampal IDO1 level. The application of 1-MT reversed the cognitive impairment, suggesting the elevated IDO1 level to be a contributing factor for the high susceptibility to AD in females with estrogen deficiency. Interestingly, E2 alleviated the cognitive function of the APP/PS1 mice undergoing OVX. E2 also decreased hippocampal IDO1 level and impacted the metabolism of IDO1-mediated L-Tryptophan (Trp)/kynurenine (Kyn) pathway by decreasing the levels of Kyn, Kyn-to-Trp ratio, 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) and increasing the levels of serotonin (5-HT), 5-HT-to-Trp ratio, and kynurenic acid (KA). The E2's effects were similar to those of the IDO1 inhibitor. Furthermore, the ERβ antagonist could reverse the effects of E2 and the ERβ agonist had comparable effects to E2 on the Trp/Kyn pathway. These findings indicate that E2 has positive effects on the cognitive function of the APP/PS1 female mice undergoing OVX, and the mechanism may be related to the modulation of IDO1-mediated Trp/Kyn pathway via activation of ERβ.