Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice

Chen Hong1,2, Zhi Wang1, Si-li Zheng1, Wen-jun Hu1, Shu-na Wang1, Yan Zhao1, Chao-yu Miao1
1 Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai 200433, China
2 Present address: State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
Correspondence to: Chao-yu Miao:,
DOI: 10.1038/s41401-022-01009-y
Received: 1 April 2022
Accepted: 25 September 2022
Advance online: 13 October 2022


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.
Keywords: Metrnl; aging; cognitive impairment; BDNF; hippocampus; astrocytes

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