Glucocorticoid-mediated activation of GSK3β promotes tau phosphorylation and impairs memory in type 2 diabetes

Dey, Aditi; Hao, Shuai; Wosiski‐Kuhn, Marlena; Stranahan, Alexis M.

doi:10.1016/j.neurobiolaging.2017.05.010

Cited by 62 publications

(42 citation statements)

References 61 publications

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“…Here, we found a significant activation of GSK3β in htau/STZ mice, as levels of phosphor‐GSK3β were reduced. These results are in concordance with previous data from our research group and others (Dey, Hao, Wosiski‐Kuhn, & Stranahan, ), where we showed that T1DM led to the activation of GSK3β and tau hyperphosphorylation (Abbondante et al, ). We have also evaluated other main tau kinases such as CDK5, ERK, and CaMKII implicated in abnormal tau phosphorylation in the brain (Mondragón‐Rodríguez et al, ).…”

Section: Discussionsupporting

confidence: 94%

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

et al. 2019

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Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule‐associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain‐of‐function and loss‐of‐function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild‐type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.

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Section: Discussionsupporting

confidence: 94%

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

et al. 2019

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“…A recent study on hippocampal slices pre-treated with an inhibitor of transcription activity showed a non-genomic activation of GSK-3β by GC. 87 The efficacy of the sGRm suggests that it is able to antagonize also non-genomic GR signaling. Of note, involvement of membrane-localized GR was linked to AD not only for the regulation of GSK-3β 88 but also-surprisingly-in the regulation of BACE1.…”

Section: F I G U R Ementioning

confidence: 99%

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

et al. 2019

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Abbreviations: Aβ, amyloid-β peptide; ADAM10, A disintegrin and metalloproteinase domain-containing protein 10 (α-secretase); APP, amyloid precursor AbstractDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid-β oligomers (oAβ), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation.We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAβ impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAβ potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of | 1153 CANET ET Al.

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“…Several studies have reported that GSK3β is a potential therapeutic target in several human diseases, such as neuronal degenerative diseases, cardiovascular disease, and cancers, that are mostly associated with metabolic reprogramming and autophagy activation. It was claimed that GSK3β induces autophagy by activating β‐catenin to regulate adiposity in the development of type 2 diabetes mellitus and suppressing mTOR in ischemic rat heart . In our study, inhibition of GSK3β induced autophagy, which promoted antinecrosis and anti‐apoptosis in liver I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Kong

Hua

Qin

et al. 2018

Hepatology Research

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Aim: Autophagy has been found to play an important role in hepatic ischemia/reperfusion (I/R) injury. Our previous study has also clarified that rictor deficiency aggravated hepatic I/R injury by suppressing autophagy. Here, we explore whether autophagy participates in glycogen synthase kinase 3β (GSK3β)mediated cytoprotection in liver I/R. Methods:Mice were treated with SB216763 to inhibit GSK3β before being subjected to hepatic I/R. Liver injury was evaluated by liver and blood samples. Autophagy was measured by detecting expression of microtubule-associated protein 1 light chain-3B (LC3B) II and autophagy protein 5 (ATG-5), as well as the number of autophagosomes by transmission electron microscope. Primary hepatocytes pretreated with SB216763 for 2 h were subjected to hypoxia/reoxygenation to induce autophagy. The lactate dehydrogenase level was used to evaluate cell death and survival. Autophagy inhibitors and 5 0 adenosine monophosphate-activated protein kinase (AMPK) inhibitor were given in vivo or in vitro. Results: SB216763 significantly increased the number of autophagosomes and the protein levels of LC3B II and ATG-5 in liver I/R models, which was accompanied by a decline of hepatic necrosis and apoptosis. Consistent with the in vivo study, autophagy and cytoprotection were induced by the inhibition of GSK3β in the in vitro study. Moreover, pretreatment with autophagy inhibitors attenuated the cytoprotective role of autophagy in the GSK3β-treated liver I/R models. Further analysis showed that pretreatment with an AMPK inhibitor increased mammalian target of rapamycin (mTOR) activity, decreased autophagy, and abrogated GSK3β-mediated liver protection.Conclusion: Autophagy was induced by GSK3β inhibition through the AMPK/mTOR pathway and could substantially ameliorate liver I/R injury. Therefore, our findings strongly renew the therapeutic value of the GSK3β/autophagy axis in hepatic I/R injury.

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Glucocorticoid-mediated activation of GSK3β promotes tau phosphorylation and impairs memory in type 2 diabetes

Cited by 62 publications

References 61 publications

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

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