Serpina1e mediates the exercise-induced enhancement of hippocampal memory

The exercise-induced enhancement of learning and memory is thought to be regulated by body‒brain interactions via secretory proteins in the blood plasma ^1,2 . Given the prominent role that skeletal muscle plays during exercise, the beneficial effects of exercise on cognitive functions appear to be mediated by muscle-derived secretory factors including myokines ^3,4 . However, the specific myokines that exert beneficial effects on cognitive functions remain to be elucidated. Here, we reveal that a novel myokine, Serpina1e, acts a molecular mediator that directly supports long-term memory formation in the hippocampus. Using an in vivo myokine-labeling mouse model, proteomic analysis revealed that the Serpina1 family of proteins are the myokines whose levels increased the most in plasma after chronic aerobic exercise for 4 weeks. Systemic delivery of recombinant Serpina1e into sedentary mice was sufficient for reproducing the beneficial effect of exercise on hippocampus-associated cognitive functions. Moreover, plasma Serpina1e can cross the blood–cerebral spinal fluid (CSF) barrier and blood–brain barrier to reach the brain, thereby influencing hippocampal function. Indeed, an increase in the plasma level of Serpina1e promoted hippocampal neurogenesis, increased the levels of brain-derived neurotrophic factor (BDNF) and induced neurite growth. Our findings reveal that Serpina1e is a myokine that migrates to the brain and mediates exercise-induced memory enhancement by triggering neurotrophic growth signaling in the hippocampus. This discovery elucidates the molecular mechanisms underlying the beneficial effects of exercise on cognitive function and may have implications for the development of novel therapeutic interventions for alleviating cognitive disorders.