Peripheral Hyperinsulinemia Promotes Tau Phosphorylation In Vivo

Freude, S.; Plum, Leona; Schnitker, Jessika; Leeser, Uschi; Udelhoven, Michael; Krone, Wilhelm; Brüning, Jens C.; Schubert, Markus

doi:10.2337/diabetes.54.12.3343

Cited by 138 publications

(94 citation statements)

References 47 publications

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“…In contrast with the protective effects of physiological insulin, hyperinsulinaemia can sensitise neurons to toxin and stress-induced insults in culture [38]. Also, peripheral high-dose insulin injection in mice causes a rapid and dose-dependent increase in tau phosphorylation in the CNS [39], a hallmark of Alzheimer's disease. In this way, too much or too little insulin in the brain could enhance neurodegenerative processes.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

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

et al. 2012

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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-feedingevoked 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; n024), standard chow (SC; n016), HF + metformin (144 mg/kg in diet; n020) or SC + metformin (144 mg/kg in diet; n016) 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.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

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

et al. 2012

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“…Also the results coming from in vivo studies with mice are not unequivocal. Both hyperinsulinemia (18) and streptozotocin-induced insulin deficiency (19) increased the phosphorylation of Tau protein in brains.…”

Section: Discussionmentioning

confidence: 95%

Coupling of Mammalian Target of Rapamycin with Phosphoinositide 3-Kinase Signaling Pathway Regulates Protein Phosphatase 2A- and Glycogen Synthase Kinase-3β-dependent Phosphorylation of Tau

Meske

Albert

Ohm

2008

Journal of Biological Chemistry

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Tau is an important microtubule-stabilizing protein in neurons. In its hyperphosphorylated form, Tau protein loses its ability to bind to microtubules and then accumulates and is part of pathological lesions characterizing tauopathies, e.g. Alzheimer disease. Glycogen synthase kinase-3␤ (GSK-3␤), antagonized by protein phosphatase 2A (PP2A), regulates Tau phosphorylation at many sites. Diabetes mellitus is linked to an increased risk of developing Alzheimer disease. This could be partially caused by dysregulated GSK-3␤. In a long term experiment (؊16 h) using primary murine neuron cultures, we interfered in the insulin/phosphoinositide 3-kinase (PI3K) (LY294002 treatment and insulin boost) and mammalian target of rapamycin (mTor) (AICAR and rapamycin treatment) signaling pathways and examined consequent changes in the activities of PP2A, GSK-3␤, and Tau phosphorylation. We found that the coupling of PI3K with mTor signaling, in conjunction with a regulatory interaction between PP2A and GSK-3␤, changed activities of both enzymes always in the same direction. These balanced responses seem to ensure the steady Tau phosphorylation at GSK/PP2A-dependent sites observed over a long period of time (>6 h). This may help in preventing severe changes in Tau phosphorylation under conditions when neurons undergo transient fluctuations either in insulin or nutrient supply. On the other hand, the investigation of Tau protein at Ser-262 showed that interference in the insulin/PI3K and mTor signaling potentially influenced the Tau phosphorylation status at sites where only one of two enzymes (in this case PP2A) is involved in the regulation.

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“…Male ND-fed reporter mice at the age of approximately 12 weeks were starved overnight, anesthetized, and intravenously injected with either saline or 5 U of human regular insulin (Novo Nordisk) for 10 and 20 minutes. As previously described, peripheral intravenous injection of human regular insulin strongly activates insulin receptor signaling in the brain with a maximum in Akt phosphorylation at 10 minutes and almost basal phosphorylated Akt (pAkt) levels at 20 minutes after the injection, with no effect on blood glucose levels during this time (49). Mice were then perfused transcardially with physiologic saline solution, frozen in tissuefreezing medium (Jung Tissue Freezing Medium; Leica Microsystems) and sectioned on a cryostat.…”

Section: Figure 10mentioning

confidence: 99%

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

Plum

Ma²,

Hampel³

et al. 2006

Journal of Clinical Investigation

290

269

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Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol 3,4,5 -trisphosphate-mediated (PIP 3 -mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP 3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (K ATP ) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the K ATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP 3 -mediated signals are critical regulators of the melanocortin system via modulation of K ATP channels.

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Peripheral Hyperinsulinemia Promotes Tau Phosphorylation In Vivo

Cited by 138 publications

References 47 publications

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

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

Coupling of Mammalian Target of Rapamycin with Phosphoinositide 3-Kinase Signaling Pathway Regulates Protein Phosphatase 2A- and Glycogen Synthase Kinase-3β-dependent Phosphorylation of Tau

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

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