​​Selenium and exercise: new insights into the hippocampal neurogenesis

Hippocampus is one of the key brain regions for learning and memory formation. Multiple studies demonstrated that adult neurogenesis (formation of new neurons) in various species, including humans, occurs in particular hippocampus areas, facilitating life-long neuroplasticity. A distinctive feature of the neural precursor cells (NPC) in the hippocampal region is their ability to start proliferation in response to physical stimuli, such as exercise.

Selenium is a micronutrient crucial for maintaining normal brain function. Selenium deficiency results in a range of age-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Aging has also been associated with a natural decline in selenium status.

Leiter et al. sought to decipher regulating mechanisms by which exercise regulates adult hippocampal neurogenesis. Their previous research identified 68 proteins that are systematically released to blood in response to exercise in mice. Among these proteins, twenty-five mammalian proteins carried selenocysteine residues. The most upregulated of those was selenoprotein P (SEPP1), with levels in the plasma of exercising mice twice higher than those of control. Though most selenoproteins carry single selenocysteine, SEPP1 carries 10 of those residues. Such number of selenocysteines allows it to supply the brain with selenium through interaction with low-density lipoprotein receptor-related protein 8 (LRP8) at the blood-brain barrier. Blood SEPP1 levels increase is activity-dependent and suggests a potential role of selenium in the activation of NPCs.

In their novel study, Leiter et al. demonstrated that an increase in selenium transport (mediated by SEPP1) boosts adult hippocampal neurogenesis. They conveyed an experiment in mice testing an influence of 4- and 2-day running regimens, and the results confirmed a significant systemic increase in SEPP1 and a corresponding increase in the number of activated NPCs. Further investigation of NPC treatment with supplementary selenium demonstrated a substantial increase in cell proliferation in vitro. Comparison of young and aged animals showed that NPC proliferation was significantly reduced in the aged hippocampus. But after the administration of selenium, the magnitude of NPC activation was also much more extensive for the older individuals. The authors also determined that mimicking the effect of exercise by dietary selenium supplementation can reverse the cognitive decline associated with hippocampal injury.

Identifying the mechanism behind the exercise-induced neurogenesis could facilitate novel therapeutic interventions (including dietary selenium supplementation), which could mimic the beneficial effects of exercise. However, to determine the translational potential of these findings, more data are needed. The main source of the released SEPP1 remains unknown, and there is a range of other regulatory proteins involved in the exercise-induced increase in neurogenesis – cathepsin B, platelet factor 4, insulin-like growth factor 1, and others. Future research will have to explain how these factors interact and whether they affect the same NPCs.

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