transforming-growth-factor-beta and Schizophrenia

Schizophrenia is a severe psychiatric disorder, with heritability around 80%, but a not fully understood pathophysiology. Signal transduction through the mothers against decapentaplegic (SMADs) are eight different proteins involved in the regulation of inflammatory processes, cell cycle, and tissue patterning. The literature is not consistent regarding the differential expression of SMAD genes among subjects with schizophrenia. In this article, we performed a systematic meta-analysis of the expression of SMAD genes in 423 brain samples (211 schizophrenia vs. 212 healthy controls), integrating 10 datasets from two public repositories, following the PRISMA guidelines. We found a statistically significant up-regulation of SMAD1, SMAD4, SMAD5, and SMAD7, and a tendency for up-regulation of SMAD3 and SMAD9 in brain samples of patients with schizophrenia. Overall, six of the eight genes showed a tendency for up-regulation, and none of them was found to have a tendency for down-regulation. SMAD1 and SMAD4 were up-regulated also in blood samples of 13 individuals with schizophrenia versus eight healthy controls, suggesting the SMAD genes' potential role as biomarkers of schizophrenia. Furthermore, SMAD genes' expression levels were significantly correlated with those of Sphingosine-1-phosphate receptor-1 (S1PR1), which is known to regulate inflammatory processes. Our meta-analysis supports the involvement of SMAD genes in the pathophysiology of schizophrenia through their role in inflammatory processes, as well as demonstrates the importance of gene expression meta-analysis for improving our understanding of psychiatric diseases.

Topics: Brain; Humans; Schizophrenia; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are specific to a subgroup of patients. To address this, we examine whether antipsychotic-naïve first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan's unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-α (TNFα) (VR = 0.36), interleukin-1β (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFα (g = 0.56), interferon-γ (IFNγ) (g = 0.32), transforming growth factor-β (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNγ, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.

Topics: C-Reactive Protein; Case-Control Studies; Cytokines; Humans; Interferon-gamma; Interleukin-17; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Leukocyte Count; Lymphocyte Count; Models, Statistical; Prodromal Symptoms; Psychotic Disorders; Schizophrenia; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

In recent years evidence has accumulated that the activity of the signaling cascades of Neuregulin-1, Wnt, TGF-beta, BDNF-p75 and DISC1 is different between control subjects and patients with schizophrenia. These pathways are involved in embryonic and adult neurogenesis and neuronal maturation. A review of the clinical data indicates that in schizophrenia the Wnt pathway is most likely hypoactive, whereas the Nrg1-ErbB4, the TGF-beta- and the BDNF-p75-pathways are hyperactive. Haplo-insuffiency of the DISC1 gene is currently the best established schizophrenia risk factor. Preclinical experiments indicate that suppression of DISC1 signaling leads to accelerated dendrite development in neuronal stem cells, accelerated migration and aberrant integration into the neuronal network. Other preclinical experiments show that increasing NRG1-, BDNF- and TGF-beta signaling and decreasing Wnt signaling, also promotes adult neuronal differentiation and migration. Thus deviations in these pathways detected in schizophrenia could contribute to premature neuronal differentiation, accelerated migration and inappropriate insertion into the neuronal network. Initial clinical findings are confirmatory: neuronal stem cells isolated from nasal biopsies from schizophrenia patients display signs of accelerated development, whilst increased erosion of telomeres and bone age provide further support for accelerated cell maturation in schizophrenia.

Topics: Age Determination by Skeleton; Animals; Brain-Derived Neurotrophic Factor; Cell Differentiation; ErbB Receptors; Humans; Intercellular Signaling Peptides and Proteins; Mice; Nerve Tissue Proteins; Neuregulin-1; Neurogenesis; Receptor, ErbB-4; Receptors, Nerve Growth Factor; Risk Factors; Schizophrenia; Signal Transduction; Stem Cells; Telomere; Transforming Growth Factor beta; Wnt Proteins

Several studies have shown that there is an imbalance between T helper 1 (Th1) cytokines and T helper 2 (Th2) cytokines in patients with schizophrenia. The T helper 3 (Th3) cytokine, transforming growth factor beta-1 (TGF-beta1), has been shown to suppress the production of Th1 cytokines. Therefore it is hypothesized that it may play a role in schizophrenia by suppressing overactive Th1 system.. We recruited 88 schizophrenic patients and 88 matched controls. The basal plasma concentrations of IFN-gamma (Th1), IL-4 (Th2) and TGF-beta1 (Th3) were studied at the time the patients were admitted to the hospital and following 8 weeks of treatment with antipsychotics.. The detection rate of plasma IFN-gamma and basal plasma TGF-beta1 level were significantly higher in schizophrenic patients than in controls whereas detection rate of plasma IL-4 was lower in patients. The ratio of Th1/Th2 cytokines (IFN-gamma/IL-4) was higher in schizophrenic patients. Following the neuroleptic treatment, the IFNgamma and TGF-beta1 levels returned to control values, and IL-4 concentration rose above the control value.. Schizophrenic patients showed higher Th1/Th2 ratio which is attenuated by effective neuroleptic treatment. It is possible that TGF-beta1 plays a role in reducing the activity of Th1 cytokine.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cytokines; Female; Humans; Interferon-gamma; Interleukin-4; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor beta s (TGF beta s) are potent immunosuppressive molecules released in the brain after injury. We hypothesized that TGF beta levels in cerebrospinal fluid (CSF) of schizophrenic patients would be altered because TGF beta can influence neural cell adhesion molecule (N-CAM) expression in vitro. The levels of TGF beta 1 and beta 2 in CSF of patients with schizophrenia and normal controls measured by ELISA showed no differences. There was evidence that the stability of TGF beta in CSF may be altered in schizophrenia. For a limited sample, TGF beta 1 and N-CAM concentrations were significantly correlated in normal patients (r = 0.98) but not in schizophrenics. The results do not support an active neurodegeneration or anti-inflammatory response in the central nervous system, which is reflected in the CSF of chronic schizophrenics.

Topics: Adult; Chronic Disease; Female; Humans; Male; Neural Cell Adhesion Molecules; Schizophrenia; Transforming Growth Factor beta

Although the loss of brain laterality is one of the most consistent modalities in schizophrenia (SCZ) and bipolar disorder (BD), its molecular basis remains elusive. Our limited previous studies indicated that epigenetic modifications are key to the asymmetric transcriptomes of brain hemispheres. We used whole-genome expression microarrays to profile postmortem brain samples from subjects with SCZ, psychotic BD [BD[+]] or non-psychotic BD [BD(-)], or matched controls (10/group) and performed whole-genome DNA methylation (DNAM) profiling of the same samples (3-4/group) to identify pathways associated with SCZ or BD[+] and genes/sites susceptible to epigenetic regulation. qRT-PCR and quantitative DNAM analysis were employed to validate findings in larger sample sets (35/group). Gene Set Enrichment Analysis (GSEA) demonstrated that BMP signaling and astrocyte and cerebral cortex development are significantly (FDR q < 0.25) coordinately upregulated in both SCZ and BD[+], and glutamate signaling and TGFβ signaling are significantly coordinately upregulated in SCZ. GSEA also indicated that collagens are downregulated in right versus left brain of controls, but not in SCZ or BD[+] patients. Ingenuity Pathway Analysis predicted that TGFB2 is an upstream regulator of these genes (p = .0012). While lateralized expression of TGFB2 in controls (p = .017) is associated with a corresponding change in DNAM (p ≤ .023), lateralized expression and DNAM of TGFB2 are absent in SCZ or BD. Loss of brain laterality in SCZ and BD corresponds to aberrant epigenetic regulation of TGFB2 and changes in TGFβ signaling, indicating potential avenues for disease prevention/treatment.

Topics: Adult; Autopsy; Bipolar Disorder; Brain; DNA Methylation; Epigenesis, Genetic; Epigenome; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Promoter Regions, Genetic; Psychotic Disorders; Schizophrenia; Signal Transduction; Transcriptome; Transforming Growth Factor beta; Whole Genome Sequencing

Polymorphisms in immune-inflammatory response genes are believed to impact schizophrenia susceptibility. However, it remains unknown whether immunogenetic factors play a role in the etiology of deficit schizophrenia (D-SCZ). Therefore, we genotyped four polymorphisms in genes encoding two immune system regulatory proteins (CTLA-4 rs231775 and CD28 rs3116496), interleukin-6 (IL6 rs1800795) and transforming growth factor-β (TGFB1 rs1800470) in 513 schizophrenia patients and 374 controls. The CD28 rs3116496-CC genotype and C-allele were significantly more frequent in the whole group of patients and D-SCZ patients compared to controls. Our results indicate that the CD28 rs3116496 polymorphism might impact the risk of schizophrenia, especially D-SCZ.

Topics: Adult; CD28 Antigens; CTLA-4 Antigen; Cytokines; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Schizophrenia; Transforming Growth Factor beta

Electroconvulsive therapy (ECT) is the most effective option for several psychiatric conditions, including treatment-resistant schizophrenia. However, little is known about the molecular mechanism of action of ECT. The link between inflammatory system and schizophrenia is the focus of recent studies. However, the impact of ECT on inflammatory functioning in this disorder remains elusive. Whether ECT could modulate inflammatory factors in patients with schizophrenia was examined.. Plasma levels of interleukin-4 (IL-4), transforming growth factor-β (TGF-β), myeloperoxidase (MPO), and nuclear factor-κB (NF-κB) activation were analyzed in 20 schizophrenic patients, mainly with resistant to antipsychotic medication disorders, and in 20 sex- and age-matched healthy controls. Disease severity was evaluated using the Brief Psychiatric Rating Scale. All patients were followed with measurement of the inflammatory factors before and after ECT treatment and compared with the controls.. Patients with schizophrenia had markedly raised NF-κB and but decreased TGF-β levels compared with healthy controls. On the other hand, no significant differences were found for the levels of IL-4 and MPO levels. The clinical improvement during repeated ECT was accompanied by a gradual and significant increase in IL-4 and TGF-β level, but MPO and NF-κB activation were left unaffected. Increases in TGF-β were negatively correlated with the change in Brief Psychiatric Rating Scale scores after ECT.. It is shown that ECT, while increasing the anti-inflammatory response such as the levels of IL-4 and TGF-β, it did not affect the levels of MPO and NF-κB activation in this study.

Topics: Adult; Antipsychotic Agents; Drug Resistance; Electroconvulsive Therapy; Female; Humans; Inflammation Mediators; Interleukin-4; Male; Middle Aged; Monocytes; NF-kappa B; Peroxidase; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Transforming Growth Factor beta

To identify proteins differentially expressed in schizophrenia patients, we collected 50 microl cerebrospinal fluid from 17 first-episode schizophrenia patients and 10 healthy controls.. Their proteins were separated by two-dimensional gel electrophoresis without using any depletion method and identified by mass spectrometry.. Approximately 550 spots were detected, six of which had significantly different intensities in schizophrenia compared to control specimens. We were able to validate in individual samples the upregulation of apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase by Western blot analyses and detect the downregulation of transthyretin, TGF-beta receptor type-1 and coiled-coil domain-containing protein 3 precursor.. These findings may help to elucidate the disease mechanisms and confirm the hypothesis of disturbed cholesterol and phospholipid metabolism in schizophrenia, and thus reveal the final role players. Moreover, a grouped protein expression analysis of apolipoprotein E, apolipoprotein A-I, and prostaglandin-H2 D-isomerase in cerebrospinal fluid from patients might be a potential diagnostic tool for schizophrenia.

Topics: Adult; Apolipoprotein A-I; Apolipoproteins E; Blotting, Western; Down-Regulation; Female; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Phospholipids; Prealbumin; Proteomics; Psychiatric Status Rating Scales; Reference Values; Schizophrenia; Transforming Growth Factor beta; Up-Regulation; Young Adult

Several linkage studies suggest that chromosome 5q31-32 might contain risk loci for schizophrenia (SZ). We wanted to identify susceptibility genes for schizophrenia within this region.. We saturated the interval between markers D5S666 and D5S436 with 90 polymorphic microsatellite markers and genotyped two sets of DNA pools consisting of 300 SZ patients of Bulgarian origin and their 600 parents. Positive associations were followed-up with SNP genotyping.. Nominally significant evidence for association (p < 0.05) was found for seven markers (D5S0023i, IL9, RH60252, 5Q3133_33, D5S2017, D5S1481, D5S0711i) which were then individually genotyped in the trios. The predicted associations were confirmed for two of the markers: D5S2017, localised in the SPRY4-FGF1 locus (p = 0.004) and IL9, localized within the IL9 gene (p = 0.014). Fine mapping was performed using single nucleotide polymorphisms (SNPs) around D5S2017 and IL9. In each region four SNPs were chosen and individually genotyped in our full sample of 615 SZ trios. Two SNPs showed significant evidence for association: rs7715300 (p = 0.001) and rs6897690 (p = 0.032). Rs7715300 is localised between the TGFBI and SMAD5 genes and rs6897690 is within the SPRY4 gene.. Our screening of 5q31-32 implicates three potential candidate genes for SZ: SMAD5, TGFBI and SPRY4.

Topics: Adult; Child; Chromosomes, Human, Pair 5; Extracellular Matrix Proteins; Fibroblast Growth Factor 1; Gene Pool; Genetic Linkage; Genetic Predisposition to Disease; Genotype; Humans; Intracellular Signaling Peptides and Proteins; Microsatellite Repeats; Nerve Tissue Proteins; Point Mutation; Polymorphism, Single Nucleotide; Prevalence; Schizophrenia; Smad5 Protein; Transforming Growth Factor beta

Transforming growth factor (TGF)beta plays a role in injury repair in sites surrounding brain injury. The present study tested the hypothesis that TGFbeta1 and TGFbeta2 levels in the postmortem CSF of patients with neurodegenerative disorders would be elevated compared to those in normal subjects. Free TGFbeta1 and total TGFbeta2 were measured by ELISA in postmortem ventricular cerebrospinal fluid (vCSF) of patients with Parkinson's disease (n = 30), Alzheimer's disease (n = 30), multiple sclerosis (n = 15), and schizophrenia (n = 12) and of normal controls (n = 16). In addition, albumin, IgG, and total protein in vCSF were measured. Both TGFbeta1 and TGFbeta2 were significantly different between groups (P < 0.002 and P < 0.001, respectively). Parkinson's disease vCSF showed significant increases in both TGFbeta1 (P = 0.015) and TGFbeta2 (P = 0.012) compared to normal controls. There was a trend for TGFbeta2 to be elevated in Alzheimer's disease and multiple sclerosis vCSFs, which failed to achieve significance. There were no differences between controls and schizophrenics in TGFbeta1 or TGFbeta2. Alzheimer's disease vCSF showed a significant decrease in protein compared to all other groups, which was not related to blood-brain barrier permeability, age, or autolysis differences. Evidence is presented suggesting that some TGFbeta1 may leak into the vCSF from plasma. Autopsy vCSF levels of TGFbeta isoforms were found to be distinctly different from those reported for human serum, especially for TGFbeta2, which is undetectable in plasma. These results indicate that further in vivo studies of TGFbeta2 in the CSF of Parkinson's disease patients are warranted to determine the relationship between clinical status, medication, and TGFbeta2 concentrations.

Topics: Age Factors; Aged; Aged, 80 and over; Albumins; Alzheimer Disease; Blood-Brain Barrier; Cerebral Ventricles; Cerebrospinal Fluid Proteins; Cross Reactions; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Male; Middle Aged; Multiple Sclerosis; Parkinson Disease; Schizophrenia; Sex Factors; Transforming Growth Factor beta