Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling
Publication date
2010Author
Kickstein, E.Krauss, S.
Thornhill, P.
Rutschow, D.
Zeller, R.
Sharkey, J.
Williamson, Ritchie
Fuchs, M.
Kohler, A.
Glossmann, H.
Schneider, R.
Sutherland, C.
Schweiger, S.
Keyword
Adenylate KinaseMetabolism
Alzheimer Disease
Pathology
Physiopathology
Animals
Cells
Cultured
Enzyme Inhibitors
Pharmacology
Epitopes
HeLa cells
Humans
Hypoglycemic agents
Metformin
Mice
Transgenic
Multiprotein complexes
Neurofibrillary Tangles
Neurons
Cytology
Okadaic acid
Phosphorylation
Protein Phosphatase 2
Proteins
Signal Transduction
Drug effects
TOR Serine-Threonine Kinases
Tau Proteins
REF 2014
Open Access status
closedAccess
Metadata
Show full item recordAbstract
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-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.Version
No full-text in the repositoryCitation
Kickstein 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.Link to Version of Record
https://doi.org/10.1073/pnas.0912793107Type
Articleae974a485f413a2113503eed53cd6c53
https://doi.org/10.1073/pnas.0912793107