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Proteasome Identified as the Mechanistic Link between Exercise and Neurogenesis

Review of “Proteasome activation by insulin‐like growth factor‐1/nuclear factor erythroid 2‐related factor 2 signaling promotes exercise‐induced neurogenesis” from STEM CELLS by Stuart P. Atkinson

While fascinating studies have linked physical exercise to the attenuation of brain aging and the prevention of neurodegenerative disease through the promotion of adult neurogenesis [1-3], we understand little regarding the mechanisms linking exercise to the production of new neurons by neural stem/progenitor cells. Previous studies from the research laboratories of Li Lu (Shanxi Medical University, Taiyuan, China) and Wulin Yang (Chinese Academy of Sciences, Hefei, China) linked higher proteasome activity with the self‐renewing capacity of adult neural progenitor cells [4], thereby suggesting that the activation of the proteasome could also counteract brain aging by neural progenitor cell neurogenesis. 

In their new STEM CELLS article, the authors report on their exploration of the proteasome as the mechanistic link between exercise and neurogenesis [5], establishing that exercise enhances hippocampal insulin‐like growth factor 1 (IGF‐1) signaling, which in turn elevates proteasome activity through nuclear factor erythroid 2‐related factor 2 (Nrf2)‐mediated transcription of proteasome subunit genes, which then enhances neurogenesis. 

Niu et al. studied the hippocampi of adult and middle‐aged mice following voluntary wheel running, finding that the observed acceleration in neurogenesis and improved cognition required the upregulation of proteasome activity. Further analyses also revealed that the increase in proteasome activity might derive from the increased levels of insulin‐like growth factor‐1 (IGF‐1) observed in both serum and the hippocampus. Importantly, exercise stimulates IGF-1 uptake across the blood-brain barrier [6], where it can induce the proliferation and differentiation of neural progenitor cells [7]. Subsequent in vitro experiments revealed that IGF‐1 stimulated proteasome activity in adult neural progenitor cells by promoting the nuclear translocation of nuclear factor erythroid 2‐related factor 2 (Nrf2) [8], followed by the elevated expression of certain proteasome subunits.

To confirm these findings, the authors pretreated adult mice with an IGF‐1R inhibitor before exercise; fascinatingly, this led to a reduction in exercise‐induced neurogenesis, Nrf2 nuclear translocation, and proteasome activity. Similarly, the inhibition of Nrf2 expression by bilateral intra‐hippocampal injections of recombinant adeno‐associated viral particles carrying Nrf2 small interfering RNAs also significantly suppressed exercise‐induced proteasome activation, and also attenuated cognitive function.

Overall, the authors report, for the first time, a link between physical exercise, proteasome activation in the hippocampus, and neurogenesis, and establish the general importance of proteostasis in the maintenance of optimal neural progenitor cell activity.

Can interventions in this newly described pathway improve brain health by enhancing adult neurogenesis? Stay tuned to the Stem Cells Portal to find out!

References

  1. Lerche S, Gutfreund A, Brockmann K, et al., Effect of physical activity on cognitive flexibility, depression and RBD in healthy elderly. Clinical Neurology and Neurosurgery 2018;165:88-93.
  2. Suwabe K, Byun K, Hyodo K, et al., Rapid stimulation of human dentate gyrus function with acute mild exercise. PNAS 2018;115:10487.
  3. van Praag H, Kempermann G, and Gage FH, Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neuroscience 1999;2:266-270.
  4. Zhao Y, Liu X, He Z, et al., Essential role of proteasomes in maintaining self-renewal in neural progenitor cells. Scientific Reports 2016;6:19752.
  5. Niu X, Zhao Y, Yang N, et al., Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis. STEM CELLS 2020;38:246-260.
  6. Trejo JL, Carro E, and Torres-Alemán I, Circulating Insulin-Like Growth Factor I Mediates Exercise-Induced Increases in the Number of New Neurons in the Adult Hippocampus. Journal of Neuroscience 2001;21:1628.
  7. Yuan H, Chen R, Wu L, et al., The Regulatory Mechanism of Neurogenesis by IGF-1 in Adult Mice. Molecular Neurobiology 2015;51:512-522.
  8. Corenblum MJ, Ray S, Remley QW, et al., Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period. Aging Cell 2016;15:725-736.