Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice
Open accessAbstract
Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg⁻¹ d⁻¹ metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db+mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.
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Metformin has been reported to increase production of Aβ in a cell culture model.
“metformin has been reported to increase production of Aβ in a cell culture model [84]”
From Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial (2016) · cites this paper as [84]
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- Authors
- Li, J., Deng, J., Sheng, W., & Zuo, Z.
- Affiliations
- Sun Yat-sen University (CN)
- University of Virginia (US)
- Corresponding author
- Zuo, Zhiyi
- Venue
- Pharmacology Biochemistry and Behavior
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 101
- Issue
- 4
- Pages
- 564-574
- ISSN
- 0091-3057 (ISSN-L)
- PMC
- PMC3327803
- OpenAlex
- W2066463950
- Cited by
- 260
- References
- 57
- Citations by year
- 2026: 3 · 2025: 16 · 2024: 12 · 2023: 24 · 2022: 21 · 2021: 24 · 2020: 27 · 2019: 22 · 2018: 20 · 2017: 18 · 2016: 17 · 2015: 16 · 2014: 21 · 2013: 14 · 2012: 4
- FWCI
- 11.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology Biochemistry and Behavior (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- University of Virginia
- International Anesthesia Research Society
- National Institute of General Medical Sciences (R01GM065211)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- metformin, Alzheimer's disease, type 2 diabetes, leptin resistance, obesity, db/db mice, tau phosphorylation, amyloid-beta, JNK, synaptophysin, hippocampus, cognitive impairment, spatial learning and memory, hyperglycemia
- MeSH terms
- Alzheimer Disease, Animals, Conditioning, Psychological, Diabetes Mellitus, Type 2, Disease Models, Animal, Drug Resistance, Fear, Hippocampus, Hypoglycemic Agents, Male, Memory, Metformin, Mice, Obese, Phosphorylation, Amyloid beta-Peptides, Synaptophysin, Neurofibrillary Tangles, tau Proteins, Maze Learning, Leptin, Vesicular Transport Proteins, JNK Mitogen-Activated Protein Kinases, Mice, Protein Phosphatase 2, Plaque, Amyloid
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