OBJECTIVE: Aquaporin-4 (AQP4), a key molecule for water homeostasis in the brain, is associated with adult neurogenesis, but its mechanisms regulating adult neural stem cells (aNSC) remain largely unexplored. Neuroinflammation has a relevant influence on adult neurogenesis, which is a common feature in various neurodegenerative diseases. Considering the possible link between neuroinflammation and AQP4, we speculate that AQP4 may mediate the synthesis and release of proinflammatory cytokines in glia and then indirectly regulate adult hippocampal neurogenesis. METHODS: Using AQP4 knockout mice, we investigated the effects of AQP4 on hippocampal neurogenesis after lipopolysaccharide (LPS)-induced neuroinflammation. RESULTS: We unexpectedly found that AQP4 deficiency attenuated the decrease in aNSC proliferation after systemic LPS exposure, accompanied by inhibition of glial activation and suppression of the production of proinflammatory cytokines in the hippocampus. Meanwhile, in vivo studies demonstrated that LPS-induced activated microglia did not express AQP4, indicating the impossibility of direct regulation of AQP4 to activate microglia. Furthermore, we demonstrated in vitro that AQP4 deficiency inhibited astrocyte activation and reduced the release of proinflammatory cytokines from astrocytes. CONCLUSION: Our data suggest that AQP4 mediates the suppressive effect of neuroinflammation on hippocampal neurogenesis via regulation of the astroglial response.
OBJECTIVE:Aquaporin-4 (AQP4), a key molecule for water homeostasis in the brain, is associated with adult neurogenesis, but its mechanisms regulating adult neural stem cells (aNSC) remain largely unexplored. Neuroinflammation has a relevant influence on adult neurogenesis, which is a common feature in various neurodegenerative diseases. Considering the possible link between neuroinflammation and AQP4, we speculate that AQP4 may mediate the synthesis and release of proinflammatory cytokines in glia and then indirectly regulate adult hippocampal neurogenesis. METHODS: Using AQP4 knockout mice, we investigated the effects of AQP4 on hippocampal neurogenesis after lipopolysaccharide (LPS)-induced neuroinflammation. RESULTS: We unexpectedly found that AQP4 deficiency attenuated the decrease in aNSC proliferation after systemic LPS exposure, accompanied by inhibition of glial activation and suppression of the production of proinflammatory cytokines in the hippocampus. Meanwhile, in vivo studies demonstrated that LPS-induced activated microglia did not express AQP4, indicating the impossibility of direct regulation of AQP4 to activate microglia. Furthermore, we demonstrated in vitro that AQP4 deficiency inhibited astrocyte activation and reduced the release of proinflammatory cytokines from astrocytes. CONCLUSION: Our data suggest that AQP4 mediates the suppressive effect of neuroinflammation on hippocampal neurogenesis via regulation of the astroglial response.
Authors: Leandro Castañeyra-Ruiz; Ibrahim González-Marrero; Luis G Hernández-Abad; Seunghyun Lee; Agustín Castañeyra-Perdomo; Michael Muhonen Journal: Int J Mol Sci Date: 2022-09-09 Impact factor: 6.208