Behavioral and metabolic effects of extended hippocampal overexpression of the myokine Irisin in an Alzheimers Disease mouse model

Lifestyle interventions such as exercise are promising strategies to reduce the detrimental effects faced by aging populations. In particular, the exercise-induced myokine Irisin could act as a mediator of the positive effects of exercise, even as a potential therapeutic option for Alzheimers disease (AD). However, the fundamental roles of Irisin in counteracting AD neuropathology and other effects have not been fully determined. In addition, whether centrally produced Irisin has any effects is unclear. Here we examined the neurobehavioral effects of overexpressing Irisin directly in the hippocampus of an AD transgenic mouse line (TgCRND8), using adult male mice stereotaxically injected with Irisin-AAV vector. To further mimic chronic exercise, spatial memory and exploratory behaviors were assessed using the novel object recognition (NOR)/open field test (OFT) and Y-Maze tests after 8 weeks. Our results showed that Irisin expression led to several behavioral changes, including increased grooming behavior and slightly improved spatial memory performance in short interval NOR test in Tg mice. In the Y-Maze test however, we observed an increase in time spent in familiar spaces, which could indicate heightened anxiety-like behaviors in mice injected with Irisin-AAV. In addition, we observed significant differences in body and liver size, and in circulating metabolites such as ketone bodies, that were differentially regulated in NTg or Tg mice. Overall, our findings show important neurobehavioral effects of long-lasting overexpression of the exerkine Irisin in the hippocampus. Our results also raise questions about potential detrimental effects and thus warrant further studies to fully dissect how this exercise mediator affects the brain.