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

Eva Kickstein, Sybille Krauss, Paul Thornhill, Desiree Rutschow, Raphael Zeller, John Sharkey, Ritchie Williamson, Melanie Fuchs, Andrea Koehler, Hartmut Glossmann, Rainer Schneider, Calum Sutherland, Susann Schweiger (Lead / Corresponding author)

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    232 Citations (Scopus)

    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-alpha 4 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.

    Original languageEnglish
    Pages (from-to)21830-21835
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number50
    DOIs
    Publication statusPublished - 14 Dec 2010

    Keywords

    • ALZHEIMER NEUROFIBRILLARY DEGENERATION
    • HELICAL FILAMENT-TAU
    • MAMMALIAN TARGET
    • DISEASE BRAIN
    • RESPIRATORY-CHAIN
    • PROTEIN-KINASE
    • CELL-GROWTH
    • MOUSE MODEL
    • RAPAMYCIN
    • EXPRESSION

    Cite this

    Kickstein, E., Krauss, S., Thornhill, P., Rutschow, D., Zeller, R., Sharkey, J., Williamson, R., Fuchs, M., Koehler, A., Glossmann, H., Schneider, R., Sutherland, C., & Schweiger, S. (2010). Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21830-21835. https://doi.org/10.1073/pnas.0912793107