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Biguanide metforminacts on tauphosphorylation viamTOR/proteinphosphatase 2A (PP2A)signaling Eva KicksteinSybille KraußPaul Thornhill2010 год

Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling
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Аннотация: 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.
Год издания: 2010
Авторы: Eva Kickstein, Sybille Krauß, Paul Thornhill, Désirée Rutschow, Raphael Zeller, John Sharkey, Ritchie Williamson, Melanie Fuchs, Andrea Köhler, Hartmut Glossmann, Rainer Schneider, Calum Sutherland, Susann Schweiger
Издательство: National Academy of Sciences
Источник: Proceedings of the National Academy of Sciences
Ключевые слова: Metabolism, Diabetes, and Cancer, Pancreatic function and diabetes, Alzheimer's disease research and treatments
Другие ссылки: Proceedings of the National Academy of Sciences (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)