Antidiabetic drug metformin (Glucophage R ) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription
Open accessAbstract
Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of beta-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of beta-amyloid (Abeta) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage(R)), affects APP metabolism and Abeta generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Abeta species. Furthermore, the effect of metformin on Abeta generation is mediated by transcriptional up-regulation of beta-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on Abeta degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on Abeta. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on Abeta generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on Abeta generation, in combined use, metformin enhances insulin's effect in reducing Abeta levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.
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One study in cellular models raises the concern that metformin might increase the risk of late onset Alzheimer's disease by increasing the generation of β-amyloid peptides through upregulation of β-secretase.
“One study in cellular models raises the concern that MET might increase the risk of late onset AD because it shows that MET increases the generation of β-amyloid peptides through upregulation of β-secretase (14)”
From Type 2 Diabetes and Antidiabetic Medications in Relation to Dementia Diagnosis (2014) · cites this paper as [14]
Metformin increases beta amyloid in cells through an AMPK-dependent mechanism independent of insulin signaling and glucose metabolism, mediated by transcriptional upregulation of BACE1.
“With regard to ß amyloid, a report has shown that metformin increases ß amyloid in cells through an AMPK-dependent mechanism, independent of insulin signaling and glucose metabolism. This effect is mediated by a transcriptional upregulation of ß secretase (BACE 1) which leads to an increase of ß amyloid [131].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [131]
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- Authors
- Chen, Y., Zhou, K., Wang, R., Liu, Y., Kwak, Y.-D., Ma, T., Thompson, R. C., Zhao, Y., Smith, L., Gasparini, L., Luo, Z., Xu, H., & Liao, F.-F.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Italian Institute of Technology (IT)
- Boston University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-10
- Volume
- 106
- Issue
- 10
- Pages
- 3907-3912
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2656178
- OpenAlex
- W1988821503
- Cited by
- 390
- References
- 54
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 11 · 2023: 13 · 2022: 22 · 2021: 33 · 2020: 28 · 2019: 25 · 2018: 24 · 2017: 26 · 2016: 25 · 2015: 26 · 2014: 33 · 2013: 22 · 2012: 29
- FWCI
- 15.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- National Institute on Aging (R01AG030197, R01AG021173)
- National Institute of Neurological Disorders and Stroke (R01NS046673, R01NS054880)
- 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 › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metformin, Alzheimer's disease, amyloid-beta, BACE1, beta-secretase, APP processing, AMPK, insulin, type 2 diabetes, insulin-sensitizing drugs, compound C, insulin-like growth factor, tyrosine kinase inhibitors, glucose deprivation
- MeSH terms
- Alzheimer Disease, Animals, Base Sequence, Binding Sites, Enzyme Activation, Glucose, Hypoglycemic Agents, Insulin, Metformin, Molecular Sequence Data, Peptides, Promoter Regions, Genetic, Transcription, Genetic, Signal Transduction, Up-Regulation, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Rats, Amyloid Precursor Protein Secretases, AMP-Activated Protein Kinases
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