Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription

Yaomin Chen, Kun Zhou, Ruishan Wang, Yun Liu, Young Don Kwak, Tao Ma, Robert C. Thompson, Yongbo Zhao, Layton Smith, Laura Gasparini, Zhijun Luo, Huaxi Xu, Francesca-Fang Liao

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Abstract

Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of β-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of β-amyloid (Aβ) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (GlucophageR), affects APP metabolism and Aβ 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 Aβ species. Furthermore, the effect of metformin on Aβ generation is mediated by transcriptional up-regulation of β-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on Aβ 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 Aβ. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on Aβ generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on Aβ generation, in combined use, metformin enhances insulin's effect in reducing Aβ levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.

Original languageEnglish (US)
Pages (from-to)3907-3912
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number10
DOIs
StatePublished - Mar 10 2009

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Metformin
Hypoglycemic Agents
Amyloid
Peptides
AMP-Activated Protein Kinases
Insulin
Amyloid beta-Protein Precursor
Alzheimer Disease
Tyrphostins
Somatomedin Receptors
Serum Amyloid A Protein
Amyloid Precursor Protein Secretases
Protein Kinase Inhibitors
Type 2 Diabetes Mellitus
Up-Regulation
Pharmacology
Neurons
Glucose

All Science Journal Classification (ASJC) codes

  • General

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Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. / Chen, Yaomin; Zhou, Kun; Wang, Ruishan; Liu, Yun; Kwak, Young Don; Ma, Tao; Thompson, Robert C.; Zhao, Yongbo; Smith, Layton; Gasparini, Laura; Luo, Zhijun; Xu, Huaxi; Liao, Francesca-Fang.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 10, 10.03.2009, p. 3907-3912.

Research output: Contribution to journalArticle

Chen, Yaomin ; Zhou, Kun ; Wang, Ruishan ; Liu, Yun ; Kwak, Young Don ; Ma, Tao ; Thompson, Robert C. ; Zhao, Yongbo ; Smith, Layton ; Gasparini, Laura ; Luo, Zhijun ; Xu, Huaxi ; Liao, Francesca-Fang. / Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 10. pp. 3907-3912.
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