https://orcid.org/0000-0002-1758-0983
Abstract
Physical exercise-induced enhancement of learning and memory and alleviation of age-related cognitive decline in humans have been widely acknowledged. However, the mechanistic relationship between exercise and cognitive improvement remains largely unknown. In this study, we found that exercise-elicited cognitive benefits were accompanied by adaptive hippocampal proteasome activation. Voluntary wheel running increased hippocampal proteasome activity in adult and middle-aged mice, contributing to an acceleration of neurogenesis that could be reversed by intrahippocampal injection of the proteasome inhibitor MG132. We further found that increased levels of insulin-like growth factor-1 (IGF-1) in both serum and hippocampus may be essential for exercise-induced proteasome activation. Our in vitro study demonstrated that IGF-1 stimulated proteasome activity in cultured adult neural progenitor cells (NPCs) by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), followed by elevated expressions of proteasome subunits such as PSMB5. In contrast, pretreating adult mice with the selective IGF-1R inhibitor picropodophyllin diminished exercise-induced neurogenesis, concurrent with reduced Nrf2 nuclear translocation and proteasome activity. Likewise, lowering Nrf2 expression by RNA interference with bilateral intrahippocampal injections of recombinant adeno-associated viral particles significantly suppressed exercise-induced proteasome activation and attenuated cognitive function. Collectively, our work demonstrates that proteasome activation in hippocampus through IGF-1/Nrf2 signaling is a key adaptive mechanism underlying exercise-related neurogenesis, which may serve as a potential targetable pathway in neurodegeneration.
It has been shown that voluntary exercise causes hippocampal proteasome activation to improve adult neural progenitor cells activity. Mechanistically, exercise induces the increase of insulin-like growth factor 1 (IGF-1) in serum and hippocampus, which in turn triggers the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to promote the expression of the key proteasome subunit PSMB5 to enhance adult neurogenesis. The present study reveals novel insights into the modulation of adult neurogenesis through proteasome activation, which could be achieved by targeting the IGF-1/Nrf2 signaling pathway.
