Global ETD Search

201	Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling 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. January 2010 (has links) No / 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. Adenylate Kinase Metabolism 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
202	A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin McNeilly, A.D., Williamson, Ritchie, Balfour, D.J., Stewart, C.A., Sutherland, C. January 2012 (has links) No / AIMS/HYPOTHESIS: We previously demonstrated that animals fed a high-fat (HF) diet for 10 weeks developed insulin resistance and behavioural inflexibility. We hypothesised that intervention with metformin would diminish the HF-feeding-evoked cognitive deficit by improving insulin sensitivity. METHODS: Rats were trained in an operant-based matching and non-matching to position task (MTP/NMTP). Animals received an HF (45% of kJ as lard; n = 24), standard chow (SC; n = 16), HF + metformin (144 mg/kg in diet; n = 20) or SC + metformin (144 mg/kg in diet; n = 16) diet for 10 weeks before retesting. Body weight and plasma glucose, insulin and leptin were measured. Protein lysates from various brain areas were analysed for alterations in intracellular signalling or production of synaptic proteins. RESULTS: HF-fed animals developed insulin resistance and an impairment in switching task contingency from matching to non-matching paradigm. Metformin attenuated the insulin resistance and weight gain associated with HF feeding, but had no effect on performance in either MTP or NMTP tasks. No major alteration in proteins associated with insulin signalling or synaptic function was detected in response to HF diet in the hypothalamus, hippocampus, striatum or cortex. CONCLUSIONS/INTERPRETATION: Metformin prevented the metabolic but not cognitive alterations associated with HF feeding. The HF diet protocol did not change basal insulin signalling in the brain, suggesting that the brain did not develop insulin resistance. These findings indicate that HF diet has deleterious effects on neuronal function over and above those related to insulin resistance and suggest that weight loss may not be sufficient to reverse some damaging effects of poor diet. Alzheimer Disease Drug therapy Metabolism Animals Behavior Drug effects Physiology Body weight Brain Cognition disorders Conditioning Operant Dietary fats Pharmacology Disease models Hormones Blood Hypoglycemic agents Insulin resistance Leptin Male Metformin Nerve tissue proteins Rats Wistar Signal transduction Treatment failure REF 2014

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

A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin