Myokine irisin is a critical regulator of cognitive function II

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. We have developed a novel approach to ascertain the transcriptional program of newborn neurons by selectively labeling the nuclei of newborn neurons using a GFP-reporter retrovirus driven by a synapsin-promotor (RV-SYN-GTRgp), followed by FACS-sorting isolated nuclei for next-gen RNA-sequencing (RNA-seq). This approach yielded 200-500 immature neuron nuclei per mouse. This novel approach was used to assess the transcriptome of newborn neurons from FNDC5 KO mice (F5KO) and wildtype littermates (WT). Mice were housed either with or without a running wheel. Therefore, we have four groups in this experiment: WT-sedentary, WT-running, F5KO-sedentary, and F5KO-running.