GSE174210
Myokine irisin is a critical regulator of cognitive function I
Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KOs, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral administration, resulting in enrichment of central irisin, was sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD. Overall design: To evaluate the therapeutic potential of peripherally delivered irisin, 8-month-old male APP/PS1 mice received AAV8-irisin-FLAG or AAV8-GFP via tail vein injections to overexpress irisin in the liver and moderately increase circulating irisin levels. Two months later, the micro-dissected hippocampi were analyzed by RNA-seq.