TrkB phosphorylation in serum extracellular vesicles correlates with cognitive function enhanced by ergothioneine in humans

Abstract

Oral administration of the food-derived antioxidant amino acid ergothioneine (ERGO) results in its efficient distribution in the brain and enhanced cognitive function. However, the effect of ERGO deficiency on cognitive impairment and the underlying mechanisms remain unknown. We revealed that cognitive function and hippocampal neurogenesis were lower in mice fed an ERGO-free diet than in those fed the control diet. Furthermore, ERGO supplementation to achieve the control diet ERGO levels reversed these effects and restored ERGO concentrations in the plasma and hippocampus. The ERGO-induced recovery of cognitive function and hippocampal neurogenesis was blocked by TrkB inhibition, with a concomitant reduction in hippocampal phosphorylated TrkB, suggesting the involvement of TrkB activation in these events. Phosphorylated TrkB was also detected in extracellular vesicles (EVs) derived from serum samples of volunteers who had been orally administered ERGO-containing tablets (5 mg/day for 12 weeks). Importantly, the ratio of serum EV-derived phosphorylated TrkB was significantly higher in the ERGO-treated group than in the placebo-treated group and was positively correlated with both serum ERGO concentrations and several cognitive domain scores from Cognitrax. Altogether, TrkB phosphorylation is involved in ERGO-induced cognitive enhancement, and TrkB phosphorylation levels in serum EVs may quantitatively represent ERGO-induced cognitive enhancement in humans.