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The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling

Kickstein, Eva, Krauss, Sybille, Thornhill, Paul, Rutschow, Désirée, Zeller, Raphael, Sharkey, John, Williamson, Ritchie, Fuchs, Melanie, Köhler, Andrea, Glossmann, Hartmut, Schneider, Rainer, Sutherland, Calum, Schweiger, Susann·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0912793107
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Abstract

Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments ( i ) metformin induces PP2A activity before and at lower levels than AMPK activity and ( ii ) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-α4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.

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  • Metformin inhibits mTOR.

    “inhibition of mTOR (Kickstein et al., 2010; Nair et al., 2014; Pérez-Revuelta et al., 2014)”

    From Metformin as a tool to target aging (2016) · cites this paper as Kickstein et al., 2010

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Research works printed but not linked: 31

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Metadata

Authors
Kickstein, E., Krauss, S., Thornhill, P., Rutschow, D., Zeller, R., Sharkey, J., Williamson, R., Fuchs, M., Köhler, A., Glossmann, H., Schneider, R., Sutherland, C., & Schweiger, S.
Affiliations
  • Max-Planck Institute for Molecular Genetics,14195 Berlin, Germany;
  • Biomedical Research Institute, Medical School, University of Dundee, DD1 9SY Dundee, United Kingdom;
  • Division of Medical Sciences, Medical School, University of Dundee, DD1 9SY Dundee, United Kingdom; and
  • Institute for Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria;
  • Institute for Biochemical Pharmacology, University of Innsbruck, 6020 Innsbruck, Austria;
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-11-22
Volume
107
Issue
50
Pages
21830-21835
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.0912793107
Cited by
380
References
6
Language
en

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