Abstract
Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induced aging cell model in vitro, Metrnl levels in the hippocampal astrocytes were significantly increased, and Metrnl knockdown and overexpression regulated the BDNF levels in primary hippocampal astrocytes rather than in neurons. We conclude that Metrnl regulates cognitive functions and hippocampal BDNF levels during aging process. As a neurotrophic factor and an endogenous protein, Metrnl is expected to become a new candidate for the treatment or alleviation of aging-related cognitive dysfunction.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (â„–82104166, â„–81730098 and â„–82030110), Medical Innovation Major Project (â„–16CXZ009), and Shanghai Science and Technology Commission Project (â„–21140901000).
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CH and ZW performed most of the experiments and data analyses and wrote the paper. SLZ, WJH, SNW and YZ performed some experiments and/or data analysis. CYM designed the study, performed data analysis, and wrote and revised the paper.
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Hong, C., Wang, Z., Zheng, Sl. et al. Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice. Acta Pharmacol Sin 44, 741–751 (2023). https://doi.org/10.1038/s41401-022-01009-y
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DOI: https://doi.org/10.1038/s41401-022-01009-y
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