Glycogen Synthase Kinase-3β Gene Research Articles

Chrysin loaded nanovesicles ameliorated diabetic peripheral neuropathy. Role of NGF/AKT/GSK-3β pathway

Diabetic peripheral neuropathy (DPN) is a common diabetic complication. Chrysin (CHY) has many biological properties but poor oral bioavailability. This study investigates the effect of CHY and CHY-loaded nanovesicles (CHY-NVs) on streptozotocin (STZ)-induced DPN in rats. CHY-NVs were prepared by using film hydration method. The formula with the best entrapment efficiency%, lowest particle size, highest zeta potential, and highest in vitro CHY released profile was selected, characterized by Differential scanning calorimetry, Fourier transformation infrared spectroscopy analysis, and examined by Transmission electron microscope. Acute toxicity test, pharmacokinetic study and experimental model of diabetes mellitus were performed on the selected formulation. Wistar rats were considered diabetic by administration of a single intraperitoneal dose of STZ (50 mg/kg). 48 h after STZ administration, hyperglycemic rats were randomly assigned into four groups, one group of untreated hyperglycemic rats and the other three groups received daily oral doses of unloaded NVs, CHY-NVs (25 mg/kg), and CHY-NVs (50 mg/kg), respectively for 21 days. Moreover, five additional groups of healthy rats received: distilled water (control), free CHY, unloaded NVs, and CHY-NVs respectively for 21 days. CHY and CHY-NVs maintained body weight and reduced STZ-induced behavioral changes in rotarod, hind paw cold allodynia, tail cold allodynia, tail flick, and hot plate tests. CHY and CHY-NVs lowered blood glucose, glycated hemoglobin, elevated serum reduced glutathione (GSH), and reduced plasma malondialdehyde (MDA) levels. CHY-NVs elevated phosphatidylinositol 3-kinase (Pi3k), phosphorylated protein kinase B (p-AKT), and reduced nuclear factor kappa B (NF-κB), interleukin-6 (IL-6) in sciatic nerve homogenate. CHY and CHY-NVs increased nerve growth factor (NGF) and decreased glycogen synthase kinase-3β (GSK-3β) gene expressions in the sciatic nerve. In conclusion, CHY and CHY-NVs ameliorated STZ-induced DPN behavioral and histopathological changes via attenuating hyperglycemia, exerting anti-oxidant, anti-inflammatory effects, activating NGF/p-AKT/GSK-3β pathway, and its anti-apoptotic effect. The best pharmacokinetic profile and therapeutic effect was observed in rats treated with CHY-loaded NVs.

The platelet derived growth factor BB promotes osteogenic differentiation of periodontal ligament stem cells via the Wnt/β-catenin signaling pathway

ObjectiveTo determine the role of platelet derived growth factor BB in the regulation of cell cycle, migration and differentiation of stem cells. DesignThe gene was overexpressed in periodontal ligament stem cells using lentiviral vectors. Normal stem cells and empty lentiviral vectors-transfected were used as controls. Real time-PCR, western blotting, Cell Counting Kit-8 assay, flow cytometry, cell scratch test, Alkaline phosphatase activity assay, cell cycle analyses were conducted to assess the biological properties of stem cells. In addition, the effect of platelet derived growth factor BB on the Wnt/β-catenin signaling pathway were assessed by western blotting and immunofluorescent staining. ResultsThe gene was successfully overexpressed in periodontal ligament stem cells. The Cell Counting Kit-8, scratch test and cell cycle experiments proved that platelet derived growth factor BB promoted stem cells proliferation, migration and cell cycle progression. The Real time-PCR results showed that the Osterix (OSX) and Bone Morphogenetic Protein 2 (BMP2) genes in the overexpression group were significantly higher than those in the control group, but the Peroxisome Proliferators-activated Receptors (PPARγ) and Glycogen Synthase Kinase-3β (GSK-3β) gene were lower than that in the control group. Western blotting results also indicated that the Collagen Type 1 (COL-1), BMP2, Wnt1 and β-catenin proteins were increased in the overexpression group. In addition, the expression level of β-catenin protein in the cell nuclei was higher than that in the control group. ConclusionsIn conclusion, overexpression of platelet derived growth factor BB promoted cell proliferation, migration, cell cycle progression and decreased adipogenic differentiation. Furthermore, platelet derived growth factor BB regulated osteogenic differentiation of stem cells through the Wnt/β-catenin signaling pathway.

Interactions Between Glycogen Synthase Kinase-3β Gene Polymorphisms, Negative Life Events, and Susceptibility to Major Depressive Disorder in a Chinese Population.

Background: Recent studies suggest that glycogen synthase kinase (GSK)-3β is involved in the development of major depressive disorder (MDD). The aim of this study was to investigate the interaction between GSK-3β polymorphism (rs6438552, rs334558, and rs2199503) and negative life events in the pathogenesis of major depressive disorder (MDD).Methods: DNA genotyping was performed on peripheral blood leukocytes in 550 patients with MDD and 552 age- and gender-matched controls. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). A chi-square method was employed to assess the gene-environment interaction (G × E).Results: Differences in rs6438552, rs334558, and rs2199503 genotype distributions were observed between MDD patients and controls. Significant G × E interactions between allelic variation of rs6438552, rs334558, and rs2199503 and negative life events were observed. Individuals with negative life events and carrying genotypes of rs6438552 A+, rs334558 A+, and rs2199503G+ have increased the risk of depression.Conclusions: These results indicate that interactions between the GSK-3β rs6438552, rs334558, and rs2199503 polymorphisms and environment increases the risk of developing MDD.

Panax Notoginseng Saponin Attenuates Gastric Mucosal Epithelial Cell Injury Induced by Dual Antiplatelet Drugs through COX and PI3K/Akt/ VEGF-GSK-3β-RhoA Network Pathway.

To elucidate the underlying mechanism of Panax notoginseng saponin (PNS) on gastric epithelial cell injury and barrier dysfunction induced by dual antiplatelet (DA). Human gastric mucosal epithelial cell (GES-1) was cultured and divided into 4 groups: a control, a DA, a PNS+DA and a LY294002+PNS+DA group. GES-1 apoptosis was detected by flow cytometry, cell permeability were detected using Transwell, level of prostaglandins E2 (PGE2), 6-keto-prostaglandin F1α (6-keto-PGF1α) and vascular endothelial growth factor (VEGF) in supernatant were measured by enzyme linked immunosorbent assay (ELISA), expression of phosphatidylinositide 3-kinase (PI3K), phosphorylated-PI3K (p-PI3K), Akt, phosphorylated-Akt (p-Akt), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), glycogen synthase kinase-3β (GSK-3β) and Ras homolog gene family member A (RhoA) were measured by Western-blot. DA induced apoptosis and hyper-permeability in GES-1, reduced supernatant level of PGE2, 6-keto-PGF1α and VEGF (P<0.05). Addition of PNS reduced the apoptosis of GES-1 caused by DA, restored the concentration of PGE2, 6-keto-PGF1α and VEGF (P<0.05). In addition, PNS attenuated the alteration of COX-1 and COX-2 expression induced by DA, up-regulated p-PI3K/p-Akt, down-regulated RhoA and GSK-3β. LY294002 mitigated the effects of PNS on cell apoptosis, cell permeability, VEGF concentration, and expression of RhoA and GSK-3β significantly. PNS attenuates the suppression on COX/PG pathway from DA, alleviates DA-induced GES-1 apoptosis and barrier dysfunction through PI3K/Akt/ VEGF-GSK-3β-RhoA network pathway.

Preventive electroacupuncture reduces cognitive deficits in a rat model of D-galactose-induced aging.

Acupuncture can reduce cognitive deficits in Alzheimer's disease. However, whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood. Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline. Therefore, we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications. A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks. Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration. Preventive electroacupuncture alleviated memory impairment, decreased tau hyperphosphorylation, and reduced glycogen synthase kinase-3β protein and mRNA expression levels in the brainstem dorsal raphe nucleus, where intracellular neurofibrillary tangle lesions first occur. In addition, the DNA methylation level in the promoter region of the glycogen synthase kinase-3β gene was increased. The effects of preventive electroacupuncture were stronger than those of preventive acupuncture. Intraperitoneal injection of 0.4 mg/kg 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase that blocks epigenetic modifications, antagonized the effects of preventive electroacupuncture. Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3β gene in the dorsal raphe nucleus. This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine, China (approval No. HUCMS201712001) on November 28, 2017.

Brain Volume-Related Polymorphisms of the Glycogen Synthase Kinase-3β Gene and Their Effect on Antidepressant Treatment in Major Depressive Disorder

Background: Glycogen synthase kinase-3β (GSK-3β) polymorphisms are known to influence hippocampal brain tissue volume in individuals with major depressive disorder (MDD). However, the effects of the GSK-3β gene single nucleotide polymorphisms (SNPs) in those receiving antidepressant therapy are unknown. Objectives: In the present study, we examined the relationship between brain volume-related SNPs of the GSK-3β gene and antidepressant treatment effects in patients with MDD. Methods: Paroxetine, fluvoxamine, or milnacipran was administered to 143 Japanese patients with MDD. Two SNPs of the GSK-3β gene (rs6438552 and rs12630592) that influence brain volume in the hippocampus were genotyped. For the primary outcome, the relationship between genetic variations in the SNPs and the percent change in the Hamilton Rating Scale for Depression (HAM-D) score at week 6 was examined. In addition, rs334558, which has been reported repeatedly, was also genotyped. Results: There was a significant correlation between the two SNPs and the percent change in the HAM-D scores at week 6 (rs6438552 A/A vs. A/G + G/G: p = 0.016; rs12630592 G/G vs. G/T + T/T: p = 0.016). There was high linkage disequilibrium between the rs6438552 and rs12630592 SNPs. The correlation between high therapeutic response over time and the two SNPs were also confirmed (rs6438552 A/A vs. others: p = 0.031; rs12630592 G/G vs. others: p = 0.031). Conclusions: Our results suggest that two GSK-3β variants that influence brain volume were associated with changes in the HAM-D scores at week 6 in patients with MDD.

Modulation of brain insulin signaling in Alzheimer’s disease: New insight on the protective role of green coffee bean extract

Objective: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD.Methods: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration.Results: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3β (GS3Kβ) gene expression and Tau hyperphosphorylation.Discussion: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.

The gender-specific association of rs334558 in GSK3β with major depressive disorder.

Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses with a heritability ranging from 40% to 50%. The single nucleotide polymorphism (SNP) rs334558 on the glycogen synthase kinase-3β (GSK3β) gene has been identified as a genetic risk loci associated with schizophrenia and bipolar disorder. However, results from replication studies examining the association between rs334558 and MDD remain inconsistent.In the present study, first, we conducted a meta-analysis of the association between rs334558 and MDD by combining 5 available case-control samples totaling 2311 cases and 2535 controls. Second, genotyping data from patients with MDD at our institution, after further stratification by gender, were analyzed to determine the association between rs334558 and MDD.All studies retrieved and included in the meta-analysis were from Korea and China. The meta-analysis suggested that the functional polymorphism rs334558 within the GSK3β promoter region was associated with MDD risk (P < 0.05). The associations were observed both in the allelic and genetic models. Analysis of the genotyping data extracted from our hospital database revealed that rs334558 exhibited exclusive association with MDD in female patients (P=0.015).Our findings suggest that GSK3β rs334558 polymorphisms might be a potential risk for MDD, and females with GSK3β rs334558 polymorphisms might have higher penetrance of MDD. If validated in larger scale samples and in different ethnic populations, these findings might be of value as diagnostic references for MDD.

Remifentanil Preconditioning Reduces Postischemic Myocardial Infarction and Improves Left Ventricular Performance via Activation of the Janus Activated Kinase-2/Signal Transducers and Activators of Transcription-3 Signal Pathway and Subsequent Inhibition of Glycogen Synthase Kinase-3β in Rats.

Remifentanil preconditioning attenuates myocardial ischemia reperfusion injury, but the underlying mechanism is incompletely understood. The Janus activated kinase-2 (JAK2)/signal transducers and activators of transcription-3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways are critical in both ischemic and pharmacologic preconditioning cardioprotection, which involve the inactivation of glycogen synthase kinase-3β. We hypothesized that remifentanil preconditioning confers cardioprotection via the JAK2/STAT3 and/or PI3K/Akt activation-mediated glycogen synthase kinase-3β inhibition. Pharmacologic intervention. Research laboratory. Male Sprague-Dawley rats. In vivo and in vitro treatments. Male Sprague-Dawley rats (n = 6 per group) were sham operated or subjected to myocardial ischemia reperfusion injury. The JAK2 inhibitor AG490 (3 mg/kg), the PI3K inhibitor wortmannin (15 μg/kg), or the glycogen synthase kinase-3β inhibitor SB216763 (600 μg/kg) were given before inducing in vivo myocardial ischemia reperfusion injury achieved by occluding coronary artery for 30 minutes followed by 120 minutes of reperfusion in the absence or presence of remifentanil preconditioning (6 μg/kg/min). Also, isolated rat hearts were Langendorff perfused and subjected to 30 minutes of global ischemia and 120 minutes of reperfusion without or with remifentanil preconditioning (100 ng/mL) in the presence or absence of AG490 and/or SB216763. Isolated rat cardiomyocytes and H9C2 cells were subjected to hypoxia/reoxygenation alone or in combination with AG490 (100 μM), wortmannin (100 nM), or SB216763 (3 μM) without or with remifentanil preconditioning (2.5 μM). Remifentanil preconditioning reduced postischemic myocardial infarction and hemodynamic dysfunction induced by myocardial ischemia reperfusion injury concomitant with increased phosphorylation of STAT3 at tyr-705 (p-STAT3) and glycogen synthase kinase-3β but not Akt. AG490 but not wortmannin cancelled remifentanil preconditioning cardioprotection, and SB216763 restored it despite the presence of AG490. In Langendorff-perfused hearts, AG490-mediated cancellation of remifentanil preconditioning cardioprotection in attenuating postischemic myocardial infarction and creatinine kinase-MB release was reverted by concomitant administration of SB216763. Remifentanil preconditioning also attenuated posthypoxic cardiomyocyte injury and increased p-STAT3 and glycogen synthase kinase-3β in isolated primary cardiomyocytes and H9C2 cells. STAT3 gene knockdown with specific synthetic RNA cancelled remifentanil preconditioning cardioprotection, whereas glycogen synthase kinase-3β gene knockdown, which per se did not affect STAT3 under hypoxia/reoxygenation condition, preserved remifentanil preconditioning cardioprotection regardless of STAT3 abrogation. Remifentanil preconditioning confers cardioprotection primarily via activation of JAK2/STAT3 signaling that can function independent of PI3K/Akt activation. Glycogen synthase kinase-3β is a critical downstream effector of remifentanil preconditioning cardioprotection.

Association study of glycogen synthase kinase-3β gene polymorphisms and major depressive disorder

Objective To explore the association between glycogen synthase kinase-3β (GSK-3β) rs334558 gene polymorphism and major depressive disorder (MDD) in Han Chinese. Methods Genotypes and alleles frequency of GSK-3β rs334558 polymorphism were examined in 250 patients and 300 healthy controls by the method of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). SPSS 17.0 statistical software was used for statistical analysis. Results (1) GSK-3β rs334558 locus of CC, CT+ TT genotypes and alleles frequency distribution between patient group (CC, CT+ TT genotypes: 38.4%, 61.6%.C, T alleles: 63.2%, 36.8%) and control group (CC, CT+ TT genotypes: 43.0%, 57.0%.C, T alleles: 67.2%, 32.8%) had no significant difference (χ2=1.194, P=0.275.χ2=1.895 P=0.169); (2) There were significant differences of rs334558 genotypes and alleles between patient group (CC, CT+ TT genotypes: 37.9%, 62.1%.C, T alleles: 63.5%, 36.5%) and control group (CC, CT+ TT genotypes: 51.0%, 49.0%.C, T alleles: 72.4%, 27.6%) in female (χ2=6.499, P=0.011.χ2=6.858, P=0.009). T allele was a risk factor for female MDD compared with C allele (OR=1.504, 95%CI=1.107~2.043); (3) There was no association between rs334558 polymorphism and MDD severity in female (χ2=0.519, P=0.471.χ2=0.199, P=0.656). Conclusion This study suggests that GSK-3β rs334558 polymorphism may be associated with the onset of MDD among female, and T allele may be a risk factor. But there is no association between polymorphism and severity of female MDD. Key words: Major depressive disorder; Glycogen synthase kinase-3β; Gene polymorphism

Paclitaxel-induced neuropathy: potential association of MAPT and GSK3B genotypes.

BackgroundPaclitaxel treatment produces dose-limiting peripheral neurotoxicity, which adversely affects treatment and long-term outcomes. In the present study, the contribution of genetic polymorphisms to paclitaxel-induced neurotoxicity were assessed in 21 patients, focusing on polymorphisms involved in the tau-microtubule pathway, an important target of paclitaxel involved in neurotoxicity development.MethodsPolymorphisms in the microtubule-associated protein tau (MAPT) gene (haplotype 1 and rs242557 polymorphism) and the glycogen synthase kinase-3β (GSK3β) gene (rs6438552 polymorphism) were investigated. Neurotoxicity was assessed using neuropathy grading scales, neurophysiological studies and patient questionnaires.ResultsA significant relationship between the GSK-3B rs6438552 polymorphism and paclitaxel-induced neurotoxicity was evident.ConclusionsPolymorphisms in tau-associated genes may contribute to the development of paclitaxel-induced neurotoxicity, although larger series will be necessary to confirm these findings.

Multiple alternative splicing and differential expression patterns of the glycogen synthase kinase-3β (GSK3β) gene in Schizothorax prenanti.

Glycogen synthase kinase-3 (GSK-3) is a key protein kinase involved in numerous cellular processes, including embryonic development, protein synthesis, glycogen metabolism, mitosis and apoptosis. However, our knowledge of Schizothorax prenanti GSK-3 is very limited. In this study, we cloned and characterized the S. prenanti GSK3β gene. Using qPCR, we found that the GSK3β gene was widely expressed in eleven tissues of S. prenanti and had especially high expression levels in the liver and brain. Moreover, we screened and sequenced more than 100 positive clones to identify the alternative transcripts of GSK3β. Five novel isoforms of GSK3β were identified in different S. prenanti tissues; these were different from the GSK3β isoforms previously reported in the other species. We named the five transcripts as GSK3β1, GSK3β2, GSK3β3, GSK3β4 and GSK3β5. These consisted of 1266, 1153, 902, 836 and 654 base pairs, respectively. Our studies provide useful information for further research on the S. prenanti GSK3β gene.

Multiple Alternative Splicing and Differential Expression Pattern of the Glycogen Synthase Kinase-3β (GSK3β) Gene in Goat (Capra hircus)

Glycogen synthase kinase-3β (GSK3β) has been identified as a key protein kinase involved in several signaling pathways, such as Wnt, IGF-Ι and Hedgehog. However, knowledge regarding GSK3β in the goat is limited. In this study, we cloned and characterized the goat GSK3β gene. Six novel GSK3β transcripts were identified in different tissues and designated as GSK3β1, 2, 3, 4, 5 and 6. RT-PCR was used to further determine whether the six GSK3β transcripts existed in different goat tissues. Bioinformatics analysis revealed that the catalytic domain (S_TKc domain) is missing from GSK3β2 and GSK3β4. GSK3β3 and GSK3β6 do not contain the negative regulatory sites that are controlled by p38 MAPK. Furthermore, qRT-PCR and western blot analysis revealed that all the GSK3β transcripts were expressed at the highest level in the heart, whereas their expression levels in the liver, spleen, kidney, brain, longissimus dorsi muscle and uterus were different. These studies provide useful information for further research on the functions of GSK3β isoforms.

P.2.d.008 Association study of the glycogen synthase kinase-3β gene polymorphism with kidney function in long-term lithium-treated patients

It is thought that airway inflammation is more common in obese asthmatic patients because inflammation is harder to control and does not respond well to glucocorticoid treatment.This study's aim was to investigate the effect of obesity on airway and systemic inflammation in children with asthma and to identify the biomarkers that play a role in this inflammation.The study included patients aged 6–16 years who were diagnosed with asthma in the paediatric allergy outpatient clinic of Bagcilar Training and Research Hospital in Turkey. Complete blood count parameters were compared between three groups: obese asthmatic (n = 43), obese non-asthmatic (n = 45), and non-obese non-asthmatic (control group, n = 30). Levels of high-sensitive CRP (hs-CRP), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), and matrix metalloproteinase-9 (MMP-9), and 25(OH)-vitamin D were compared between the groups.No statistically significant differences were observed in 25(OH)-vitamin D, NGAL, OPN, hs-CRP, and MMP-9 levels between groups. There was a statistically significant negative correlation between FEV1/FVC and NGAL and MMP-9.This is the first study to investigate levels of hs-CRP, NGAL, OPN, MMP-9, and 25(OH)-vitamin D in obese asthmatic children. Larger studies with sputum and BAL examinations are required to determine the potential of biomarkers for identifying inflammation in obese asthmatic children.

MiR-346 Regulates Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting the Wnt/β-Catenin Pathway

Osteogenic differentiation of human mesenchymal stem cells (hMSCs) is regulated by multiple transcription factors and signaling molecules. However, the molecular mechanisms underlying this process remain to be fully elucidated. MicroRNAs (miRNAs) act as key regulators in various biological processes by mediating mRNA degradation or translational inhibition of target genes. In this study, we report that miR-346 plays critical roles in regulating osteogenic differentiation of hBMSCs. The expression of endogenous miR-346 was increased during osteogenic differentiation of hBMSCs. Overexpression of miR-346 significantly promoted osteogenic differentiation, whereas miR-346 depletion suppressed this process. Further studies confirmed that miR-346 directly targeted the 3′-UTR of the glycogen synthase kinase-3β (GSK-3β) gene so as to suppress the expression of GSK-3β protein. Similar to miR-346 overexpression, GSK-3β depletion promoted osteogenic differentiation, whereas GSK-3β overexpression reversed the promotional effect of miR-346. We further found that miR-346 overexpression activated the Wnt/β-catenin pathway and increased the expression of several downstream genes including CyclinD1, c-Myc, TCF-1 and LEF-1. Depletion of β-catenin almost completely blocked the positive role of miR-346 on osteogenic differentiation. Taken together, our data indicate that miR-346 positively regulates hBMSC osteogenic differentiation by targeting GSK-3β and activating the Wnt/β-catenin pathway.

GSK3B and MAPT Polymorphisms Are Associated with Grey Matter and Intracranial Volume in Healthy Individuals

The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3β gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B = 0.082, 95% confidence interval = 0.037–0.128) and intracranial volume (summary B = 0.113, 95% confidence interval = 0.082–0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders.

Interaction Between the Central and Peripheral Effects of Insulin in Controlling Hepatic Glucose Metabolism in the Conscious Dog

The importance of hypothalamic insulin action to the regulation of hepatic glucose metabolism in the presence of a normal liver/brain insulin ratio (3:1) is unknown. Thus, we assessed the role of central insulin action in the response of the liver to normal physiologic hyperinsulinemia over 4 h. Using a pancreatic clamp, hepatic portal vein insulin delivery was increased three- or eightfold in the conscious dog. Insulin action was studied in the presence or absence of intracerebroventricularly mediated blockade of hypothalamic insulin action. Euglycemia was maintained, and glucagon was clamped at basal. Both the molecular and metabolic aspects of insulin action were assessed. Blockade of hypothalamic insulin signaling did not alter the insulin-mediated suppression of hepatic gluconeogenic gene transcription but blunted the induction of glucokinase gene transcription and completely blocked the inhibition of glycogen synthase kinase-3β gene transcription. Thus, central and peripheral insulin action combined to control some, but not other, hepatic enzyme programs. Nevertheless, inhibition of hypothalamic insulin action did not alter the effects of the hormone on hepatic glucose flux (production or uptake). These data indicate that brain insulin action is not a determinant of the rapid (<4 h) inhibition of hepatic glucose metabolism caused by normal physiologic hyperinsulinemia in this large animal model.

The peripheral messenger RNA expression of glycogen synthase kinase‐3β genes in Alzheimer's disease patients: a preliminary study

To explore the peripheral leucocytic messenger RNA (mRNA) expression of glycogen synthase kinase-3β (GSK-3β) gene in Alzheimer's disease (AD) patients. Using TaqMan relative quantitative real-time polymerase chain reaction, we analyzed leucocytic gene expression of GSK-3β in 48 AD patients and 49 healthy controls. Clinical data of AD patients were also collected. The mRNA expression level of the GSK-3β gene was significantly higher in the AD group (3.13±0.62) than in the normal group (2.77±0.77). Correlational analyses showed that the mRNA expression level of GSK-3β gene in AD patients was associated with the age of onset (P=0.047), age (P=0.055), and Behavioral Pathology in Alzheimer's Disease Rating Scale total score (P=0.062) and subscores: aggressiveness score (P=0.073) and anxieties and phobias score (P=0.067). Through multivariate regression model, older age, higher anxieties and phobias score and aggressiveness score were associated with higher mRNA expression level of GSK-3β gene. In AD patients, the mRNA expression level of the GSK-3β gene is increased and may be related to age and behavioural pathology in AD.

Association of a GSK-3β Polymorphism with Brain Resting-State Function in Amnestic-Type Mild Cognitive Impairment

The glycogen synthase kinase-3β (GSK-3β) gene has been implicated in Alzheimer's disease (AD). Polymorphisms in this gene are plausible modulators of brain function. However, little is known about the potential role of the GSK-3β rs334558 polymorphism, which has been associated with amnestic mild cognitive impairment (aMCI), which is itself associated with a high risk of AD. In this study, 43 aMCI patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging, and their GSK-3β rs334558 genotypes were evaluated to determine the effect of the risk variant on regional brain activity and functional networks in these subjects. Then, gene-brain-behavior relationships were examined. Compared with the controls, aMCI subjects with the higher risk T allele had more deficits in regional activation of the right superior frontal gyrus (rSFG), while a higher functional connectivity of the rSFG was observed in TT/CT carriers. Further correlative analyses revealed that the increase in rSFG connectivity was robustly positively correlated with non-memory performance in aMCI GSK-3β rs334558 TT/CT carriers. Our findings are the first to show that a clinically significant proportion of resting-state brain function variation in aMCI patients may be explained by genetic variation at the GSK-3βrs334558 locus in ways that are distinguishable from controls.

Glycogen synthase kinase 3β gene polymorphisms may be associated with bipolar I disorder and the therapeutic response to lithium

BackgroundGlycogen Synthase Kinase 3β (GSK-3β) is thought to be a key feature in the therapeutic mechanism of mood stabilizers (e.g., lithium). Overexpression of GSK-3β might play a role in the pathogenesis of bipolar I disorder. Within the GSK-3β gene, a promoter single nucleotide polymorphism (SNP) rs334558 was identified associated with transcriptional strength, and an intronic SNP rs6438552 was found to regulate selection of splice acceptor sites. The aim of this study is to test the association between the two polymorphisms and bipolar I disorder. MethodsWe genotyped the two SNPs in 138 Taiwanese bipolar I disorder patients and 131 controls. Lithium treatment efficacy was evaluated for 83 patients who had been treated with lithium carbonate for at least 24 months. ResultsWe found no association between each of the two SNPs and the risk of bipolar I disorder. Following correction for multiple testing, CT genotype at rs6438552 was associated with an older age of onset than other genotypes (P=0.042) in female patients. Patients with genotype TT at rs334558 (P=0.044) had poorer response to lithium treatment. There was a trend that haplotype C-T increased the risk for bipolar I disorder (adjusted OR=4.22, corrected P=0.084), and patients with haplotype T-T had poorer treatment response to lithium than those with haplotype C-C. LimitationsLimitations included small sample size, retrospective data collection, and a potential sampling bias. ConclusionsDespite the several limitations of the study, our results suggested GSK-3β genetic variants may be associated with the risk of bipolar I disorder, age of disease onset in females, and the therapeutic response to lithium.