Show simple item record

dc.contributor.authorKickstein, E.*
dc.contributor.authorKrauss, S.*
dc.contributor.authorThornhill, P.*
dc.contributor.authorRutschow, D.*
dc.contributor.authorZeller, R.*
dc.contributor.authorSharkey, J.*
dc.contributor.authorWilliamson, Ritchie*
dc.contributor.authorFuchs, M.*
dc.contributor.authorKohler, A.*
dc.contributor.authorGlossmann, H.*
dc.contributor.authorSchneider, R.*
dc.contributor.authorSutherland, C.*
dc.contributor.authorSchweiger, S.*
dc.date.accessioned2014-04-28T10:50:43Z
dc.date.available2014-04-28T10:50:43Z
dc.date.issued2010
dc.identifier.citationKickstein E, Krauss S, Thornhill P et al (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.
dc.identifier.urihttp://hdl.handle.net/10454/6051
dc.description.abstractHyperphosphorylated 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-alpha4 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.
dc.relation.isreferencedbyhttp://dx.doi.org/10.1073/pnas.0912793107
dc.subjectAdenylate Kinase; Metabolism
dc.subject; Alzheimer Disease; Pathology; Physiopathology
dc.subject; Animals
dc.subject; Cells; Cultured
dc.subject; Enzyme Inhibitors; Pharmacology
dc.subject; Epitopes
dc.subject; HeLa cells
dc.subject; Humans
dc.subject; Hypoglycemic agents
dc.subject; Metformin
dc.subject; Mice
dc.subject; Transgenic
dc.subject; Multiprotein complexes
dc.subject; Neurofibrillary Tangles
dc.subject; Neurons; Cytology
dc.subject; Okadaic acid
dc.subject; Phosphorylation
dc.subject; Protein Phosphatase 2
dc.subject; Proteins
dc.subject; Signal Transduction; Drug effects
dc.subject; TOR Serine-Threonine Kinases
dc.subject; Tau Proteins
dc.subject; REF 2014
dc.titleBiguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling
dc.typeArticle


This item appears in the following Collection(s)

Show simple item record