Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy
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BACKGROUND: Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. Epidemiological and experimental evidence suggests a clear link between type 2 diabetes mellitus and AD. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance and diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy. However, their efficacy for tauopathy in vivo has not been tested. RESULTS: Here, we report that in the P301S mutant human tau (P301S) transgenic mouse model of tauopathy, chronic administration of metformin exerts paradoxical effects on tau pathology. Despite reducing tau phosphorylation in the cortex and hippocampus via AMPK/mTOR and PP2A, metformin increases insoluble tau species (including tau oligomers) and the number of inclusions with β-sheet aggregates in the brain of P301S mice. In addition, metformin exacerbates hindlimb atrophy, increases P301S hyperactive behavior, induces tau cleavage by caspase 3 and disrupts synaptic structures. CONCLUSIONS: These findings indicate that metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action, possibly leading to an overall increase of the risk of tauopathy in elderly diabetic patients.
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Caspase-3 cleavage leads to dissociation of tau from microtubules, and enhanced tau aggregation.
“Caspase-3 cleavage leads to the dissociation of tau from microtubules, and enhanced tau aggregation [130, 191, 195].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [195]
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- Authors
- Barini, E., Antico, O., Zhao, Y., Asta, F., Tucci, V., Catelani, T., Marotta, R., Xu, H., & Gasparini, L.
- Affiliations
- Italian Institute of Technology (IT)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Gasparini, Laura
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2016-02-09
- Volume
- 11
- Issue
- 1
- Pages
- 16-16
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC4746897
- OpenAlex
- W2257327272
- Cited by
- 126
- References
- 82
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 8 · 2023: 16 · 2022: 18 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 7 · 2017: 12 · 2016: 9
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01AG021173, R01AG038710, R01AG044420, and R01NS046673)
- Alzheimer's Association
- The Tanz Family Funds
- National Natural Science Foundation of China (91332114 and U1405222)
- Istituto Italiano di Tecnologia
- 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 › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- metformin, tauopathy, tau aggregation, P301S tau transgenic mice, Alzheimer's disease, type 2 diabetes, tau phosphorylation, AMPK/mTOR signaling, protein phosphatase 2A, tau oligomers, β-sheet aggregates, hyperactive behavior, caspase-3, insulin resistance, antidiabetic drugs
- MeSH terms
- Animals, Behavior, Animal, Brain, Disease Models, Animal, Metformin, Mice, Transgenic, tau Proteins, Tauopathies, Mice
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