title: Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling.
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.
authors.affiliation: Max-Planck Institute for Molecular Genetics,14195 Berlin, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kickstein
authors.forename: Sybille
authors.initials: S
authors.lastname: Krauss
authors.forename: Paul
authors.initials: P
authors.lastname: Thornhill
authors.forename: Désirée
authors.initials: D
authors.lastname: Rutschow
authors.forename: Raphael
authors.initials: R
authors.lastname: Zeller
authors.forename: John
authors.initials: J
authors.lastname: Sharkey
authors.forename: Ritchie
authors.initials: R
authors.lastname: Williamson
authors.forename: Melanie
authors.initials: M
authors.lastname: Fuchs
authors.forename: Andrea
authors.initials: A
authors.lastname: Köhler
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glossmann
authors.forename: Rainer
authors.initials: R
authors.lastname: Schneider
authors.forename: Calum
authors.initials: C
authors.lastname: Sutherland
authors.forename: Susann
authors.initials: S
authors.lastname: Schweiger
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000939:Epitopes; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D000939:Epitopes; D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D011506:Proteins; D016875:tau Proteins; D019319:Okadaic Acid; D008687:Metformin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D054648:Protein Phosphatase 2