CIDeRplusGeneral Information:
| Id: | 6,898 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance |
| Mus musculus | |
| P301S mutant human tau (P301S) transgenic mouse model of tauopathy | |
| article | |
| Reference: | Barini E et al.(2016) Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy Mol Neurodegener 11: 16 [PMID: 26858121] |
Interaction Information:
| Comment | P301S mice, a transgenic mouse model of tauopathy, show neither peripheral nor brain insulin resistance. |
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Formal Description Interaction-ID: 67331 |
organism model P301S mouse NOT increases_activity of disease Insulin resistance |
| Comment | Levels of insulin receptor (IR)-beta mRNA, IR precursor, and IR-beta protein were similar in P301S and age-matched WT mice. Cortical levels of both IRS1 and its form phosphorylated on Serine 616, which indicates insulin resistance, were also similar in P301S and WT mice. Levels of AKT and mTOR and their active forms phosphorylated on Serine 473 and Serine 2448, respectively, were unchanged in P301S mice cortex. Signaling was similarly unchanged in the hippocampus. |
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Formal Description Interaction-ID: 67923 |
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| Drugbank entries | Show/Hide entries for INSR |
| Comment | Levels of insulin receptor (IR)-beta mRNA, IR precursor, and IR-beta protein were similar in P301S and age-matched WT mice. Cortical levels of both IRS1 and its form phosphorylated on Serine 616, which indicates insulin resistance, were also similar in P301S and WT mice. Levels of AKT and mTOR and their active forms phosphorylated on Serine 473 and Serine 2448, respectively, were unchanged in P301S mice cortex. Signaling was similarly unchanged in the hippocampus. |
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Formal Description Interaction-ID: 67927 |
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| Drugbank entries | Show/Hide entries for IRS1 |
| Comment | Levels of insulin receptor (IR)-beta mRNA, IR precursor, and IR-beta protein were similar in P301S and age-matched WT mice. Cortical levels of both IRS1 and its form phosphorylated on Serine 616, which indicates insulin resistance, were also similar in P301S and WT mice. Levels of AKT and mTOR and their active forms phosphorylated on Serine 473 and Serine 2448, respectively, were unchanged in P301S mice cortex. Signaling was similarly unchanged in the hippocampus. |
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Formal Description Interaction-ID: 67928 |
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| Drugbank entries | Show/Hide entries for AKT1 |
| Comment | Levels of insulin receptor (IR)-beta mRNA, IR precursor, and IR-beta protein were similar in P301S and age-matched WT mice. Cortical levels of both IRS1 and its form phosphorylated on Serine 616, which indicates insulin resistance, were also similar in P301S and WT mice. Levels of AKT and mTOR and their active forms phosphorylated on Serine 473 and Serine 2448, respectively, were unchanged in P301S mice cortex. Signaling was similarly unchanged in the hippocampus. |
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Formal Description Interaction-ID: 67929 |
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| Drugbank entries | Show/Hide entries for MTOR |
| Comment | Levels of insulin receptor (IR)-beta mRNA, IR precursor, and IR-beta protein were similar in P301S and age-matched WT mice. Cortical levels of both IRS1 and its form phosphorylated on Serine 616, which indicates insulin resistance, were also similar in P301S and WT mice. Levels of AKT and mTOR and their active forms phosphorylated on Serine 473 and Serine 2448, respectively, were unchanged in P301S mice cortex. Signaling was similarly unchanged in the hippocampus. |
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Formal Description Interaction-ID: 67930 |
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| Comment | Metformin reduces tau phosphorylation in the brain of P301S mice. |
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Formal Description Interaction-ID: 67931 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Total tau protein levels were similar in P301S mice with or without metformin, both in the cortex and hippocampus. |
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Formal Description Interaction-ID: 67932 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Physiological phosphorylation of tau depends on the balance between protein kinase and phosphatase activity. Protein phosphatase 2A (PP2A) is the main tau-targeting protein phosphatase, while among kinases, glycogen synthase kinase 3beta (GSK3beta) plays a key role in insulin-regulated tau phosphorylation. Metformin increases PP2A expression in the brain of P301S mice. Chronic treatment with metformin alters neither GSK3beta protein expression nor phosphorylation levels of GSK3beta at Ser9, indicating that metformin does not inhibit GSK3beta activity. |
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Formal Description Interaction-ID: 67934 |
drug/chemical compound increases_quantity of complex/PPI Protein phosphatase 2A |
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Physiological phosphorylation of tau depends on the balance between protein kinase and phosphatase activity. Protein phosphatase 2A (PP2A) is the main tau-targeting protein phosphatase, while among kinases, glycogen synthase kinase 3beta (GSK3beta) plays a key role in insulin-regulated tau phosphorylation. Metformin increases PP2A expression in the brain of P301S mice. Chronic treatment with metformin alters neither GSK3beta protein expression nor phosphorylation levels of GSK3beta at Ser9, indicating that metformin does not inhibit GSK3beta activity. |
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Formal Description Interaction-ID: 67935 |
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| Drugbank entries | Show/Hide entries for Metformin or GSK3B |
| Comment | Protein phosphatase 2A (PP2A) is regulated by the integration of several intracellular signals, including the insulin signaling pathway and/or inhibition of mTOR through phosphorylation by AMPK. In P301S mice, chronic treatment with metformin slightly, but significantly increased AMPK protein expression and strongly enhanced its activation. |
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Formal Description Interaction-ID: 67937 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Protein phosphatase 2A (PP2A) is regulated by the integration of several intracellular signals, including the insulin signaling pathway and/or inhibition of mTOR through phosphorylation by AMPK. Metformin inhibits mTOR signaling in the brain of P301S mice. |
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Formal Description Interaction-ID: 67938 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | The results suggest that chronic administration of metformin inhibits mTOR and activates AMPK in the brain of P301S mice, without affecting insulin signaling. |
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Formal Description Interaction-ID: 67940 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | To examine PP2A involvement, cortical neurons were treated with metformin alone or in combination with the PP2A inhibitor, okadaic acid (OA). OA alone increased the levels of tau phosphorylation, without changing total tau expression. When co-incubated, OA abolished metformin-induced tau dephosphorylation in primary neurons indicating that metformin’s effect on tau phosphorylation requires PP2A activity. |
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Formal Description Interaction-ID: 67941 |
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| Comment | To examine PP2A involvement, cortical neurons were treated with metformin alone or in combination with the PP2A inhibitor, okadaic acid (OA). OA alone increased the levels of tau phosphorylation, without changing total tau expression. When co-incubated, OA abolished metformin-induced tau dephosphorylation in primary neurons indicating that metformin’s effect on tau phosphorylation requires PP2A activity. |
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Formal Description Interaction-ID: 67942 |
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| Comment | To examine PP2A involvement, cortical neurons were treated with metformin alone or in combination with the PP2A inhibitor, okadaic acid (OA). OA alone increased the levels of tau phosphorylation, without changing total tau expression. When co-incubated, OA abolished metformin-induced tau dephosphorylation in primary neurons indicating that metformin’s effect on tau phosphorylation requires PP2A activity. |
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Formal Description Interaction-ID: 67943 |
drug/chemical compound decreases_activity of drug/chemical compound |
| Drugbank entries | Show/Hide entries for |
| Comment | The authors investigated whether reducing tau phosphorylation translates into amelioration of tau filamentous inclusions. The amount of insoluble tau, both monomeric and oligomeric, was significantly increased in metformin-treated P301S mice. Despite reducing tau phosphorylation, chronic treatment with metformin significantly increases the formation of insoluble aggregates with beta-sheet secondary structure in vivo. |
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Formal Description Interaction-ID: 67944 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | The authors investigated whether reducing tau phosphorylation translates into amelioration of tau filamentous inclusions. The amount of insoluble tau, both monomeric and oligomeric, was significantly increased in metformin-treated P301S mice. Despite reducing tau phosphorylation, chronic treatment with metformin significantly increases the formation of insoluble aggregates with beta-sheet secondary structure in vivo. |
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Formal Description Interaction-ID: 67948 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin increases hyperactive behavior in P301S mice. |
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Formal Description Interaction-ID: 67950 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | To examine the effects of metformin treatment on neurodegeneration, the hindlimb extension reflex, which is as an index of motor neuron degeneration, was evaluated throughout the 4-month treatment period. Metformin treatment exacerbates hindlimb extension reflex deficit in P301S mice. |
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Formal Description Interaction-ID: 67951 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Caspase 3 cleaves tau protein at Asp421 forming a cleaved-tau (c-Tau) fragment, which facilitates tau filament formation in vitro and in vivo and has detrimental effects on synaptic structures. Metformin treatment induces activation of caspase 3 and cleavage of tau in primary cortical neurons and in the P301S mouse brain. |
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Formal Description Interaction-ID: 67952 |
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| Drugbank entries | Show/Hide entries for Metformin or CASP3 |
| Comment | In cultured neurons, metformin treatment induces caspase 3 activation, increased levels of caspase 3 cleavage products cleaved Tau (c-Tau) and cleaved PARP (c-PARP) and reduces the expression of post-synaptic density 95 (PSD95). |
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Formal Description Interaction-ID: 67955 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | In cultured neurons, metformin treatment induces caspase 3 activation, increased levels of caspase 3 cleavage products cleaved Tau (c-Tau) and cleaved PARP (c-PARP) and reduces the expression of post-synaptic density 95 (PSD95). |
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Formal Description Interaction-ID: 67958 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | In cultured neurons, metformin treatment induces caspase 3 activation, increased levels of caspase 3 cleavage products cleaved Tau (c-Tau) and cleaved PARP (c-PARP) and reduces the expression of post-synaptic density 95 (PSD95). |
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Formal Description Interaction-ID: 67959 |
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| Drugbank entries | Show/Hide entries for Metformin or DLG4 |
| Comment | Despite levels of synapsin I and PSD95 were unchanged, the expression of synaptophysin was significantly reduced in P301S mice treated with metformin. |
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Formal Description Interaction-ID: 67960 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action, possibly leading to an overall increase of the risk of tauopathy in elderly diabetic patients. |
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Formal Description Interaction-ID: 67962 |
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| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action, possibly leading to an overall increase of the risk of tauopathy in elderly diabetic patients. |
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Formal Description Interaction-ID: 67965 |
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| Drugbank entries | Show/Hide entries for Metformin |