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Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer's model mice.

التفاصيل البيبلوغرافية
العنوان: Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer's model mice.
المؤلفون: Cho SY; Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.; Department of Psychiatry, Laboratory for Alzheimer's Molecular Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.; Metabolism-Dementia Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea., Kim EW; Graduate School of Medicine, Yonsei University, Seoul, 03722, Republic of Korea.; Department of Nursing, Seoyeong University, Gwangju, 61268, Republic of Korea., Park SJ; Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea.; Research Institute for Agricultural and Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea., Phillips BU; Department of Psychology, The University of Cambridge, Cambridge, CB2 3EB, UK., Jeong J; Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.; Department of Psychiatry, Laboratory for Alzheimer's Molecular Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.; Metabolism-Dementia Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea., Kim H; Department of Psychiatry, Laboratory for Alzheimer's Molecular Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.; Metabolism-Dementia Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea., Heath CJ; School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK7 6AA, UK., Kim D; Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea., Jang Y; Interdisciplinary Program in Agricultural Genomics, Center for Food and Bioconvergence, Seoul National University, Seoul, 08826, Republic of Korea., López-Cruz L; School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK7 6AA, UK., Saksida LM; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, N6A 5K8, Canada.; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, N6A 5C1, Canada., Bussey TJ; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, N6A 5K8, Canada.; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, N6A 5C1, Canada., Lee DY; Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea.; Research Institute for Agricultural and Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea.; Interdisciplinary Program in Agricultural Genomics, Center for Food and Bioconvergence, Seoul National University, Seoul, 08826, Republic of Korea., Kim E; Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. eosu.kim@yonsei.ac.kr.; Department of Psychiatry, Laboratory for Alzheimer's Molecular Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. eosu.kim@yonsei.ac.kr.; Metabolism-Dementia Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. eosu.kim@yonsei.ac.kr.; Graduate School of Medicine, Yonsei University, Seoul, 03722, Republic of Korea. eosu.kim@yonsei.ac.kr.
المصدر: Translational psychiatry [Transl Psychiatry] 2024 Jan 18; Vol. 14 (1), pp. 34. Date of Electronic Publication: 2024 Jan 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101562664 Publication Model: Electronic Cited Medium: Internet ISSN: 2158-3188 (Electronic) Linking ISSN: 21583188 NLM ISO Abbreviation: Transl Psychiatry Subsets: MEDLINE
أسماء مطبوعة: Original Publication: New York, NY : Nature Pub. Group
مواضيع طبية MeSH: Alzheimer Disease*/metabolism , Metformin*/pharmacology , Metformin*/therapeutic use, Humans ; Mice ; Animals ; tau Proteins/metabolism ; Drug Repositioning ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Cognition ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics
مستخلص: Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer's disease (AD), also known as "type 3 diabetes". Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, β-amyloid oligomers, plaques, phosphorylated tau, and GSK3β expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP 695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 2021R1I1A1A01047462 Ministry of Education (Ministry of Education of the Republic of Korea); 2021R1I1A1A01047462 Ministry of Education (Ministry of Education of the Republic of Korea); 2021R1I1A1A01047462 Ministry of Education (Ministry of Education of the Republic of Korea); HR22C141102 Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs); HR22C141102 Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs); HR22C141102 Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs); 2022M3E5E8030792 National Research Foundation of Korea (NRF); 2022M3E5E8030792 National Research Foundation of Korea (NRF); 2022M3E5E8030792 National Research Foundation of Korea (NRF)
المشرفين على المادة: 9100L32L2N (Metformin)
0 (tau Proteins)
0 (Amyloid beta-Peptides)
0 (Amyloid beta-Protein Precursor)
تواريخ الأحداث: Date Created: 20240118 Date Completed: 20240122 Latest Revision: 20240122
رمز التحديث: 20240122
مُعرف محوري في PubMed: PMC10796941
DOI: 10.1038/s41398-024-02755-9
PMID: 38238285
قاعدة البيانات: MEDLINE
الوصف
تدمد:2158-3188
DOI:10.1038/s41398-024-02755-9