Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice
Abstract Background Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer’s disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Biology of Sex Differences |
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| Online Access: | https://doi.org/10.1186/s13293-025-00684-w |
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| author | Yingbin Lin Xinqun Luo Fangyu Wang Huange Cai Yuanxiang Lin Dezhi Kang Wenhua Fang |
| author_facet | Yingbin Lin Xinqun Luo Fangyu Wang Huange Cai Yuanxiang Lin Dezhi Kang Wenhua Fang |
| author_sort | Yingbin Lin |
| collection | DOAJ |
| description | Abstract Background Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer’s disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood. Methods ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice’s blood glucose was also recorded. Results Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice. Conclusions Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies. |
| format | Article |
| id | doaj-art-028c47665ede4ae69b5eab03700e7f0d |
| institution | Kabale University |
| issn | 2042-6410 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology of Sex Differences |
| spelling | doaj-art-028c47665ede4ae69b5eab03700e7f0d2025-01-26T12:10:45ZengBMCBiology of Sex Differences2042-64102025-01-0116111010.1186/s13293-025-00684-wSex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR miceYingbin Lin0Xinqun Luo1Fangyu Wang2Huange Cai3Yuanxiang Lin4Dezhi Kang5Wenhua Fang6Department of Neurosurgery, Neurosurgery Research Institute, Institute of Neurology, Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Binhai Branch of National Regional Medical Center, Fujian Medical UniversityDepartment of Neurosurgery, Neurosurgery Research Institute, Institute of Neurology, Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Binhai Branch of National Regional Medical Center, Fujian Medical UniversityDepartment of Neurosurgery, Neurosurgery Research Institute, Institute of Neurology, Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Binhai Branch of National Regional Medical Center, Fujian Medical UniversityDepartment of Ultrasound, The First Affiliated Hospital, Fujian Medical UniversityDepartment of Neurosurgery, Neurosurgery Research Institute, Institute of Neurology, Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Binhai Branch of National Regional Medical Center, Fujian Medical UniversityDepartment of Neurosurgery, Neurosurgery Research Institute, Institute of Neurology, Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Binhai Branch of National Regional Medical Center, Fujian Medical UniversityDepartment of Neurosurgery, Neurosurgery Research Institute, Institute of Neurology, Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Binhai Branch of National Regional Medical Center, Fujian Medical UniversityAbstract Background Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer’s disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood. Methods ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice’s blood glucose was also recorded. Results Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice. Conclusions Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies.https://doi.org/10.1186/s13293-025-00684-wApolipoprotein E4MetforminSex differenceCognitionAnxietyDepression |
| spellingShingle | Yingbin Lin Xinqun Luo Fangyu Wang Huange Cai Yuanxiang Lin Dezhi Kang Wenhua Fang Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice Biology of Sex Differences Apolipoprotein E4 Metformin Sex difference Cognition Anxiety Depression |
| title | Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice |
| title_full | Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice |
| title_fullStr | Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice |
| title_full_unstemmed | Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice |
| title_short | Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice |
| title_sort | sex differences in cognition anxiety phenotype and therapeutic effect of metformin in the aged apoe tr mice |
| topic | Apolipoprotein E4 Metformin Sex difference Cognition Anxiety Depression |
| url | https://doi.org/10.1186/s13293-025-00684-w |
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