p(HGNC:GSK3B)

Entity

Name

GSK3B

Namespace

HGNC

Namespace Version

20180215

Namespace URL

https://arty.scai.fraunhofer.de/artifactory/bel/namespace/hgnc/hgnc-20180215.belns

In a similar fashion, released AICD has been shown to possess transactivation activity and can regulate transcription of multiple genes including APP, GSK- 3b, KAI1, neprilysin, BACE1, p53, EGFR, and LRP1 [127-132] PubMed:21214928

Although Tip60 does not bind to AICD directly, an indirect interaction between AICD and Tip60 is mediated by Fe65. Upon forming this complex, AICD is stabilized and can be translocated into the nucleus to regulate expression of genes such as KAI1, Neprilysin, LRP1, p53, GSK-3b and EGF receptor (Baek et al. 2002; Kim et al. 2003; Cao and Sudhof 2004; Pardossi-Piquard et al. 2005; Alves da Costa et al. 2006; Liu et al. 2007; Zhang et al. 2007) PubMed:22122372

Another transactivating complex consisting of AICD, Fe65 and Late SV40 Factor (LSF)/leader-binding protein-1 (LBP1)/transcription factor CP2 (TFCP2) has also been reported to induce the expression of GSK3-b (Kim et al. 2003) PubMed:22122372

It has been shown that activation of M1 receptors decreases tau hyperphosphorylation via activation of PKC and inhibition of GSK-3β PubMed:26813123

In addition to inhibiting Abeta generation, activation of M1 mAChR counteracts Abeta-induced neurotoxicity through the Wnt signaling pathway, as Abeta impairs the Wnt pathway and M1 mAChR stimulation inactivates GSK-3beta via PKC activation, stabilizes beta-catenin, and induces the expression of Wnt-targeting genes engrailed and cyclin-D1 for neuron survival PubMed:24590577

In addition to inhibiting Abeta generation, activation of M1 mAChR counteracts Abeta-induced neurotoxicity through the Wnt signaling pathway, as Abeta impairs the Wnt pathway and M1 mAChR stimulation inactivates GSK-3beta via PKC activation, stabilizes beta-catenin, and induces the expression of Wnt-targeting genes engrailed and cyclin-D1 for neuron survival PubMed:24590577

For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118] PubMed:21882945

These observations indicate that AMPK negatively regulates GSK3b activity and tau phosphorylation PubMed:22419736

GSK3β is inactivated upon phosphorylation of Ser9 by protein kinase B (AKT) [41] whereas AKT phosphorylation at Ser473 results in AKT activation [42]. DOI:10.4172/2168-975X.1000126

As shown in Figure 5A and B, treatment of control cells with Ab42 reduced the levels of AMPK phosphorylation at Thr172 and the inhibitory phosphorylation of GSK3b at Ser9. On the contrary, these alterations triggered by Ab42 were not observed in SH-SY5Y/AK1 knockdown cells, showing no changes in the levels of the phosphorylated AMPK and GSK3b. These results suggest that AK1 plays a crucial role in the regulation of AMPK and GSK3b in the neuronal cells exposed to Ab42. PubMed:22419736

Cdc37 is also required for the stable folding of protein kinases in coordination with Hsp90 (Calderwood, 2015). Many of these kinases are known to phosphorylate tau at sites associated with AD, such as GSK3β and MAPK13 (Taipale et al., 2012; Jin et al., 2016). PubMed:29311797

In general, GSK-3β phosphorylation is inhibited through the canonical Wnt signalling pathway [5]. Wnt, binding to frizzled receptor, recruits dishevelled protein, which in turn antagonizes GSK-3β activity. PubMed:18494933

Western blot analysis for a panel of tau kinases showed that only the levels of endogenous Cdk5 and Akt were significantly reduced by Cdc37 siRNA; the levels of GSK3-Beta and Mark2 (microtubule affinity regulating kinase 2) were largely unchanged PubMed:21367866

GSK3Beta may directly bind to tau within a GSK3Beta-tau complex.To identify the GSK3Beta-binding region within tau, we constructed three tau deletion mutants: R-tau-(1–244) containing the N-terminal projection domain, R-tau-(245–369) containing the microtubule-binding region, and R-tau-(245–441) containing both the microtubule-binding region and the C-terminal tail. We evaluated the binding of these mutants and wild-type R-tau with GST-GSK3Beta by the GST pull-down assay. GSK3Beta bound to wild type (Fig. 5B) and R-tau-(1–244) (Fig. 5C) but not R-tau-(245–369) (Fig. 5D) and R-tau-(245–441) (Fig.5E). These data demonstrate that GSK3Beta binds to the Nterminal projection domain of tau. PubMed:11812770

These observations suggested that 14-3-3zeta may be bound to GSK3Beta and/or tau within brain microtubules and may be a component of tau phosphorylation complex.Therefore, 14-3-3 must be the central molecule that holds tau and GSK3Beta within the complex. Indeed, FLAG-tau co-immunoprecipitated with HA-GSK3Beta from cells overexpressing FLAG-tau and HA-GSK3Beta only when these cells also overexpressed Xpress-14-3-3zeta (Fig. 6A, lanes 8 and 9), indicating that GSK3Beta associates with tau only in the presence of 14-3-3zeta. As discussed above, 14-3-3zeta binds to tau (36) and GSK3Beta (Fig. 5) directly. Taken together, these observations indicated that 14-3-3zeta connects GSK3Beta to tau in vivo. PubMed:12551948

In cells that were co-transfected with fixed amounts of FLAG-tau and HA-GSK3Beta but different amounts of Xpress-14-3-3zeta, FLAG-tau phosphorylation increased progressively with the increase in the amount of Xpress-14-3-3zeta (lanes 7–9). This increase was evident not only by an increased immunoreactivity against all tau phosphorylation-sensitive antibodies tested but also by a retarded mobility of FLAG-tau on the SDS gel, a characteristic feature of hyperphosphorylated tau (2, 3). Thus, 14-3-3zeta profoundly stimulated GSK3Beta-catalyzed tau phosphorylation in vivo. PubMed:12551948

For example, ongoing inflammation can trigger various cell stress-response pathways, including overexpression of the secreted glycoprotein Dickopff-1 (DKK-1). DKK-1 up-regulates GSK-3β activity, promotes tau hyper-phosphorylation, NFT formation and neuronal degeneration. Thus, DKK-1 inhibits Wnt signalling in a manner similar to Aβ, and thereby fosters a self-sustaining feedback loop resulting in cellular injury PubMed:18494933

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Alsterpaullone showed identical results with the wild-type and the mutant enzymes, demonstrating that its mechanism of inhibition is independent of the presence of the Cys-199 residue. PubMed:22102280

Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. PubMed:10998059

Inhibition caused by hypothemycin and tideglusib on a panel of selected human recombinant kinases PubMed:22102280

We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. PubMed:28176663

We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. PubMed:28176663

We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. PubMed:28176663

ID-8 indeed showed selectivity against the CMGC kinase family, with DYRK1B, GSK3B and DYRK1A being the top three kinase targets. Although a biotinylated derivative of ID-8 bound DYRK2 and DYRK4 in affinity chromatography pull down assays (Hasegawa et al., 2012), ID-8 itself showed little activity against these kinases, or against DYRK3. Next we determined IC50 values for a subset of these kinase targets, using the same 33P incorporation assay (Table 1). PubMed:28884684

We report here that indirubins are also powerful inhibitors (IC(50): 5-50 nm) of an evolutionarily related kinase, glycogen synthase kinase-3beta (GSK-3 beta). PubMed:11013232

We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. PubMed:22102280

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

The results provide a molecular basis to explain the synergistic action of casein kinase II and GSK-3 that is also observed with native glycogen synthase. PubMed:2820993

Recently, Li et al. (2012b) have demonstrated in their study that AGEs can induce tau hyperphosphorylation through receptor for advanced glycation end product (RAGE)-mediated glycogen synthase kinase 3 (GSK-3) activation and targeting RAGE/GSK-3 pathway can improve AD-like changes. PubMed:24183963

In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. PubMed:18494933

Western blot analysis of different experimental groups, primary hippocampal neuron cells concurrent treatment with different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA for 24 h, also showed that glucose–BSA inhibited the phosphorylation of GSK-3b in a concentration-dependent manner (Fig. 4(a)). And 100 nM GLP-1 or Ex-4 can up-regulate phosphorylation of GSK-3b at Ser9, which was decreased by treatment with glucose–BSA (Fig. 4(b, c)). PubMed:24183963

The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10]. PubMed:29121589

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948

Activates cdk5 and GSK3; genetic variation protects against AD in Spanish cohort PubMed:20096481

Pro-inflammatory IL-18 increases AD-associated A beta deposition in human neuron-like cells in culture [55]. IL-18 also increases the expression of glycogen synthase kinase 3 beta (GSK-3 beta ) and cyclin-dependent kinase 5, both of which are involved in hyperphos- phorylation of the tau protein [56]. PubMed:27314526

Moreover, estradiol has been shown to inhibit tau hyperphosphorylation and can also modulate glycogen synthase kinase-3β (GSK-3β) activity, a kinase that is involved in tau phosphorylation. Estradiol deactivates GSK-3β by inducing its phosphorylation, thereafter reducing tau phosphorylation. PubMed:30444369

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Specific PP2A inhibition has been proven to lead to in vivo deregulation of many major brain Ser/Thr kinases implicated in AD, including GSK3β (Wang et al., 2010; Louis et al., 2011), cdk5 (Louis et al., 2011; Kimura et al., 2013), extracellular signal- regulated kinase (ERK) and JNK (Kins et al., 2003). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Although much further work is needed, these additional data demonstrate that GSK-3β is intimately involved in the architecture of axons and other neuronal processes, providing indirect support for its role in tau-mediated con- trol of axonal transport. PubMed:12428809

Moreover, some tau kinases as cyclin- dependent kinase 5 (cdk5) and TPKI (thiamine pyrophos- phokinase 1)/GSK3 (glycogen synthase kinase 3) are acti- vated following PP2A inhibition in starved mice [51]. PubMed:22299660

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9,Aand B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9,Aand B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Some of these enhancer genes are specific only to the tau-induced disease phenotype and include genes encoding proteins like WNT2 (111), TTBK2 (112), GSK-3b (113), TAOK1 (114, 115), CTSE (116) and CHRNA7 (117), have been implicated in tau-mediated pathology. PubMed:29191965

We have previously shown that Syk positively regulates GSK-3 β activity in vitro. PubMed:28877763

Fourth, tau can regulate the release of cargo vesicles from kinesin chains by activating PP1 and glycogen synthase kinase 3β (GSK3β) via the 18 residues at the N terminus of tau PubMed:26631930

AICD also contains three phosphorylation sites, including two threonine residues at 654 and 668 and a serine residue at 665. AICD has been found to be phosphorylated by PKC, calcium-calmodulin dependent-kinase II, GSK3-b, Cdk5 and c-Jun N-terminal kinase (JNK) at the Ser/Thr sites mentioned above PubMed:22122372

AICD also contains three phosphorylation sites, including two threonine residues at 654 and 668 and a serine residue at 665. AICD has been found to be phosphorylated by PKC, calcium-calmodulin dependent-kinase II, GSK3-b, Cdk5 and c-Jun N-terminal kinase (JNK) at the Ser/Thr sites mentioned above PubMed:22122372

AICD also contains three phosphorylation sites, including two threonine residues at 654 and 668 and a serine residue at 665. AICD has been found to be phosphorylated by PKC, calcium-calmodulin dependent-kinase II, GSK3-b, Cdk5 and c-Jun N-terminal kinase (JNK) at the Ser/Thr sites mentioned above PubMed:22122372

Glycogen synthase 3β (GSK3β) is one of the main serine-threonine kinase responsible for tau phosphorylation and has been shown to affect tau phosphorylation at multiple AD relevant epitopes including Ser396, Ser404, Thr231 and Ser202 DOI:10.4172/2168-975X.1000126

Glycogen synthase 3β (GSK3β) is one of the main serine-threonine kinase responsible for tau phosphorylation and has been shown to affect tau phosphorylation at multiple AD relevant epitopes including Ser396, Ser404, Thr231 and Ser202 DOI:10.4172/2168-975X.1000126

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions PubMed:21882945

Importantly, MARK2-based phosphorylation of tau is accelerated by the priming activity of either Cdk5 or GSK3b [29], suggesting that tau phosphorylation involves a series of ordered kinase events. PubMed:21882945

Glycogen synthase 3β (GSK3β) is one of the main serine-threonine kinase responsible for tau phosphorylation and has been shown to affect tau phosphorylation at multiple AD relevant epitopes including Ser396, Ser404, Thr231 and Ser202 DOI:10.4172/2168-975X.1000126

Glycogen synthase 3β (GSK3β) is one of the main serine-threonine kinase responsible for tau phosphorylation and has been shown to affect tau phosphorylation at multiple AD relevant epitopes including Ser396, Ser404, Thr231 and Ser202 DOI:10.4172/2168-975X.1000126

Cdc37 is also required for the stable folding of protein kinases in coordination with Hsp90 (Calderwood, 2015). Many of these kinases are known to phosphorylate tau at sites associated with AD, such as GSK3β and MAPK13 (Taipale et al., 2012; Jin et al., 2016). PubMed:29311797

GSK3Beta may directly bind to tau within a GSK3Beta-tau complex.To identify the GSK3Beta-binding region within tau, we constructed three tau deletion mutants: R-tau-(1–244) containing the N-terminal projection domain, R-tau-(245–369) containing the microtubule-binding region, and R-tau-(245–441) containing both the microtubule-binding region and the C-terminal tail. We evaluated the binding of these mutants and wild-type R-tau with GST-GSK3Beta by the GST pull-down assay. GSK3Beta bound to wild type (Fig. 5B) and R-tau-(1–244) (Fig. 5C) but not R-tau-(245–369) (Fig. 5D) and R-tau-(245–441) (Fig.5E). These data demonstrate that GSK3Beta binds to the Nterminal projection domain of tau. PubMed:11812770

GSK3Beta may directly bind to tau within a GSK3Beta-tau complex.To identify the GSK3Beta-binding region within tau, we constructed three tau deletion mutants: R-tau-(1–244) containing the N-terminal projection domain, R-tau-(245–369) containing the microtubule-binding region, and R-tau-(245–441) containing both the microtubule-binding region and the C-terminal tail. We evaluated the binding of these mutants and wild-type R-tau with GST-GSK3Beta by the GST pull-down assay. GSK3Beta bound to wild type (Fig. 5B) and R-tau-(1–244) (Fig. 5C) but not R-tau-(245–369) (Fig. 5D) and R-tau-(245–441) (Fig.5E). These data demonstrate that GSK3Beta binds to the Nterminal projection domain of tau. PubMed:11812770

These data indicated that phosphorylation of PP2A dephosphorylation sites is an important recognition signal for ubiquitination. We used 200 μg of amino-terminal His-tagged full-length recombinant human tau in an in vitro phosphorylation reaction with GSK-3Beta. When phosphorylated, the tau protein reacted on immunoblots with PHF1 (25, 26) and AT8 (24), indicating that at least sites Ser202, Thr205, Ser396, and Ser404 were phosphorylated. Following GSK-3Beta incubation, this tau served as an excellent substrate for in vitro ubiquitination using UbcH5B and the cofactor fraction from AD tau immunoprecipitates (Fig. 2a). This finding suggested that GSK-3Beta can place phosphates on tau that create recognition sites for an E3 Ub ligase. PubMed:14612456

These data indicated that phosphorylation of PP2A dephosphorylation sites is an important recognition signal for ubiquitination. We used 200 μg of amino-terminal His-tagged full-length recombinant human tau in an in vitro phosphorylation reaction with GSK-3Beta. When phosphorylated, the tau protein reacted on immunoblots with PHF1 (25, 26) and AT8 (24), indicating that at least sites Ser202, Thr205, Ser396, and Ser404 were phosphorylated. Following GSK-3Beta incubation, this tau served as an excellent substrate for in vitro ubiquitination using UbcH5B and the cofactor fraction from AD tau immunoprecipitates (Fig. 2a). This finding suggested that GSK-3Beta can place phosphates on tau that create recognition sites for an E3 Ub ligase. PubMed:14612456

These data indicated that phosphorylation of PP2A dephosphorylation sites is an important recognition signal for ubiquitination. We used 200 μg of amino-terminal His-tagged full-length recombinant human tau in an in vitro phosphorylation reaction with GSK-3Beta. When phosphorylated, the tau protein reacted on immunoblots with PHF1 (25, 26) and AT8 (24), indicating that at least sites Ser202, Thr205, Ser396, and Ser404 were phosphorylated. Following GSK-3Beta incubation, this tau served as an excellent substrate for in vitro ubiquitination using UbcH5B and the cofactor fraction from AD tau immunoprecipitates (Fig. 2a). This finding suggested that GSK-3Beta can place phosphates on tau that create recognition sites for an E3 Ub ligase. PubMed:14612456

These data indicated that phosphorylation of PP2A dephosphorylation sites is an important recognition signal for ubiquitination. We used 200 μg of amino-terminal His-tagged full-length recombinant human tau in an in vitro phosphorylation reaction with GSK-3Beta. When phosphorylated, the tau protein reacted on immunoblots with PHF1 (25, 26) and AT8 (24), indicating that at least sites Ser202, Thr205, Ser396, and Ser404 were phosphorylated. Following GSK-3Beta incubation, this tau served as an excellent substrate for in vitro ubiquitination using UbcH5B and the cofactor fraction from AD tau immunoprecipitates (Fig. 2a). This finding suggested that GSK-3Beta can place phosphates on tau that create recognition sites for an E3 Ub ligase. PubMed:14612456

In general, GSK-3β phosphorylation is inhibited through the canonical Wnt signalling pathway [5]. Wnt, binding to frizzled receptor, recruits dishevelled protein, which in turn antagonizes GSK-3β activity. PubMed:18494933

For example, ongoing inflammation can trigger various cell stress-response pathways, including overexpression of the secreted glycoprotein Dickopff-1 (DKK-1). DKK-1 up-regulates GSK-3β activity, promotes tau hyper-phosphorylation, NFT formation and neuronal degeneration. Thus, DKK-1 inhibits Wnt signalling in a manner similar to Aβ, and thereby fosters a self-sustaining feedback loop resulting in cellular injury PubMed:18494933

These observations suggested that 14-3-3zeta may be bound to GSK3Beta and/or tau within brain microtubules and may be a component of tau phosphorylation complex.Therefore, 14-3-3 must be the central molecule that holds tau and GSK3Beta within the complex. Indeed, FLAG-tau co-immunoprecipitated with HA-GSK3Beta from cells overexpressing FLAG-tau and HA-GSK3Beta only when these cells also overexpressed Xpress-14-3-3zeta (Fig. 6A, lanes 8 and 9), indicating that GSK3Beta associates with tau only in the presence of 14-3-3zeta. As discussed above, 14-3-3zeta binds to tau (36) and GSK3Beta (Fig. 5) directly. Taken together, these observations indicated that 14-3-3zeta connects GSK3Beta to tau in vivo. PubMed:12551948

In cells that were co-transfected with fixed amounts of FLAG-tau and HA-GSK3Beta but different amounts of Xpress-14-3-3zeta, FLAG-tau phosphorylation increased progressively with the increase in the amount of Xpress-14-3-3zeta (lanes 7–9). This increase was evident not only by an increased immunoreactivity against all tau phosphorylation-sensitive antibodies tested but also by a retarded mobility of FLAG-tau on the SDS gel, a characteristic feature of hyperphosphorylated tau (2, 3). Thus, 14-3-3zeta profoundly stimulated GSK3Beta-catalyzed tau phosphorylation in vivo. PubMed:12551948

The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10]. PubMed:29121589

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948

Recently, Li et al. (2012b) have demonstrated in their study that AGEs can induce tau hyperphosphorylation through receptor for advanced glycation end product (RAGE)-mediated glycogen synthase kinase 3 (GSK-3) activation and targeting RAGE/GSK-3 pathway can improve AD-like changes. PubMed:24183963

In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. PubMed:18494933

Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively. PubMed:29121589

Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. PubMed:10998059

The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10]. PubMed:29121589

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

Taken together, our results show that DMF reduces GSK-3 activity in vivo as determined by a significant and subtle reduction in the phosphorylation levels of its two substrates TAU and CRMP2 respectively. PubMed:29121589

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Vm (nM/min/mg) is 2400, 80, 106, 650, and 140; Km is 200, 59, 114, 16 (all uM) and 5mg/ml for phospho-CREB peptide, myelin basic protein, k-casein, phosphatase Inhibitor-2 and phosvitin PubMed:7514173

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. PubMed:28176663

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

By using a yeast two hybrid system, TPKI was found to interact with pyruvate dehydrogenase (PDH), which is a key enzyme in the glycolytic pathway. PDH was phosphorylated in vitro by TPKI to reduce the activity converting pyruvate into acetyl-CoA, which is required for acetylcholine synthesis. PubMed:9089387

We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes. PubMed:25331948

We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. PubMed:28176663

We found that GSK3β mRNA was overexpressed only in patients with initial AD, with no effect on the levels of the protein. On the other hand, we unexpectedly observed the decrease of the inactive GSK3β in cortex from AD patients at Braak stages I-II, whereas considerable increase was observed in AD patients at stages V-VI compared to the control subjects. PubMed:28176663

Because S199/S202/T205E, S396/S404E, 6-Phos and 7-Phos all demonstrated an AD-like shift in mobility as a result of phosphorylation-like changes, we conclude that they have the characteristics of hyperphosphorylated tau. These mutants will therefore be referred to as pseudo-hyperphosphorylated tau throughout the manuscript. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation. PubMed:19459590

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. PubMed:24355211

The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin. PubMed:25546293

The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin. PubMed:25546293

The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin. PubMed:25546293

Pro-inflammatory IL-18 increases AD-associated A beta deposition in human neuron-like cells in culture [55]. IL-18 also increases the expression of glycogen synthase kinase 3 beta (GSK-3 beta ) and cyclin-dependent kinase 5, both of which are involved in hyperphos- phorylation of the tau protein [56]. PubMed:27314526

Moreover, estradiol has been shown to inhibit tau hyperphosphorylation and can also modulate glycogen synthase kinase-3β (GSK-3β) activity, a kinase that is involved in tau phosphorylation. Estradiol deactivates GSK-3β by inducing its phosphorylation, thereafter reducing tau phosphorylation. PubMed:30444369

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

Apart from affecting tau phosphorylation, abnormal activation of GSK3β, cdk5, and ERK has been linked to cytoskeletal abnormalities (microtubules, neurofilaments), alterations in amyloid precursor protein (APP) phosphorylation and processing, impairment of neurogenesis, alterations in synaptic plasticity and induction of apoptotic processes (Reviewed in Crews and Masliah, 2010; Medina and Avila, 2013, 2014). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

For instance, activated GSK3β has been reported to induce PP2A inactivation via several mechanisms: phosphorylation of PP2A on Tyr307 (Yao et al.,2011); demethylation of PP2A on Leu309 through inhibition of LCMT1 and up-regulation of PME1 (Yao et al.,2012); and accumulation of I2 PP2A (Liu et al.,2008a). PubMed:24653673

Among the specific “proline-dependent” kinases that can phosphorylate protein tau at dif- ferent sites in vitro, special attention is dedicated to glycogen-synthase kinase-3β (GSK-3β) (Michel et al., 1998), mitogen-activated protein kinase (MAPK) (Drewes et al., 1992), stress-activated protein kinases (SAPKs) (Goedert et al., 1997) and cyclin-dependent kinases (CDKs) including cdc2 and cdk5 (Baumann et al., 1993; Patrick et al., 1999). PubMed:12428809

Neuronally overexpressed GSK-3β was demonstrated to hyperphosphorylate tau protein in vivo in the brain and spinal cord of double- transgenic mice (Spittaels et al., 2000) thereby reducing the amount of protein tau associated with microtubules by 50% (Spittaels et al., 2000). PubMed:12428809

Neuronally overexpressed GSK-3β was demonstrated to hyperphosphorylate tau protein in vivo in the brain and spinal cord of double- transgenic mice (Spittaels et al., 2000) thereby reducing the amount of protein tau associated with microtubules by 50% (Spittaels et al., 2000). PubMed:12428809

More- over, the unbound tau protein was hyperphospho- rylated and especially at the AD-2 epitope, e.g., an epitope shown to contain serine 396 and serine 404. PubMed:12428809

Surprisingly, the axonopathy was rescued in the tau x GSK-3β double-transgenic mice, together with a near-total normalization of the functional disabilities. PubMed:12428809

Although much further work is needed, these additional data demonstrate that GSK-3β is intimately involved in the architecture of axons and other neuronal processes, providing indirect support for its role in tau-mediated con- trol of axonal transport. PubMed:12428809

Tau phosphorylation, the major disease-related post-translational modification, is highly regulated by glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and other kinases. PubMed:29758300

We further confirmed that possibility by showing that Tau phosphorylation at the typical GSK3β sites (PHF-1 and CP13) is reduced following treatment of SH-SY5Y cells with BAY61-3606, whereas Tau phosphorylation at the RZ3 site was not significantly impacted in SH-SY5Y cells (Fig. 9C). PubMed:25331948

We further confirmed that possibility by showing that Tau phosphorylation at the typical GSK3β sites (PHF-1 and CP13) is reduced following treatment of SH-SY5Y cells with BAY61-3606, whereas Tau phosphorylation at the RZ3 site was not significantly impacted in SH-SY5Y cells (Fig. 9C). PubMed:25331948

We further confirmed that possibility by showing that Tau phosphorylation at the typical GSK3β sites (PHF-1 and CP13) is reduced following treatment of SH-SY5Y cells with BAY61-3606, whereas Tau phosphorylation at the RZ3 site was not significantly impacted in SH-SY5Y cells (Fig. 9C). PubMed:25331948

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91). PubMed:29191965

Some of these enhancer genes are specific only to the tau-induced disease phenotype and include genes encoding proteins like WNT2 (111), TTBK2 (112), GSK-3b (113), TAOK1 (114, 115), CTSE (116) and CHRNA7 (117), have been implicated in tau-mediated pathology. PubMed:29191965

Stimulation of GSK3β but not GSK3α promoted BACE1 gene expression and BACE1-mediated APP processing in vitro by regulating BACE1 gene promoter activity, which was dependent on NF-κB p65-binding elements in the BACE1 pro- moter [51]. PubMed:27288790