Association between polymorphisms in transforming growth factor-β1 and sporadic Alzheimer's disease in a Chinese population

Alzheimer's disease (AD) is the most common neurodegenerative disorder of the brain. It causes the slow progressive loss of cognitive functions that ultimately leads to dementia and death in the elderly. The etiology and mechanism of late-onset AD (LOAD) are poorly understood, and genetic factors might play an important role in the development of AD. The aim of this study was to investigate the association between common polymorphisms in TGF-β1 with LOAD in a Chinese Han population. Two single nucleotide polymorphisms in TGF-β1 (rs1800469 and rs1982073) were genotyped in 202 patients with sporadic LOAD and 225 control subjects using polymerase chain reaction restriction fragment length polymorphism. Our results showed that rs1800469 in TGF-β1 were significantly associated with LOAD. The frequencies of the AC genotypes of rs1800469 were significantly higher in the LOAD patients than in the control subjects (42.5% vs 28.6%; P = 0.001). The minor allele (C) frequency was significantly higher in patients with LOAD than in control subjects (30.7% vs. 21.0%; P = 0.001). The genotypes and allele of rs1982073 in TGF-β1 were also significantly associated with LOAD. The frequency of the TG genotype of rs1982073 was significantly higher in the LOAD patients than in the control subjects (38.1% vs. 27.1%; P = 0.013). The minor allele (G) frequency was significantly higher in patients with LOAD than in control subjects (22.2% vs. 16.7%; P = 0.032). These results suggest that common variants in TGF-β1 might contribute to the development of LOAD in the Chinese population.     

Relationship between the neuroprotective effects of insulin-like growth factor-1 and 17β-oestradiol in human neuroblasts

Insulin-like growth factor-1 (IGF-1) and oestrogens interact with each other as neuroprotective factors. We have previously demonstrated that 17β-oestradiol protects against β-amyloid and oxidative stress toxicity and increases the amount of cell cholesterol in human foetal neuroblasts (FNC). The present study aimed: (i) to assess the protective effects of IGF-1 in FNC cells; (ii) to investigate the relationship between IGF-1 and 17β-oestradiol; and (iii) to determine whether cholesterol was a major mediator of the effects of IGF-1, similarly to 17β-oestradiol. We found that IGF-1 effectively exerts neuroprotective effects in FNC cells. We also demonstrated that the IGF-1 receptor (IGF-1R) pathway is needed to maintain oestrogen-mediated neuroprotection. Finally, we found that, opposite to 17β-oestradiol, IGF-1 did not cause a significant increase in cell cholesterol. These findings indicate that a cross-talk between IGF-1 and 17β-oestradiol occurs in FNC cells. In particular, the activation of the IGF-1R cascade appears to be fundamental to warrant 17β-oestradiol-mediated neuroprotection, even though cell cholesterol does not play a major role as an effector of this pathway.     

Meta-analysis of the transforming growth factor-β1 polymorphisms and susceptibility to Alzheimer’s disease

The association between transforming growth factor-β1 (TGF-β1) gene polymorphisms and Alzheimer’s disease (AD) risk has been widely reported, but results were somewhat controversial and underpowered. To derive a more precise estimation of the relationship between TGF-β1 polymorphisms and AD risk, we conducted a meta-analysis of all available case–control studies relating the T869C and/or C-509T polymorphisms of the TGF-β1 gene to the risk of developing AD. Eligible articles were identified by search of databases including Pub Med, Web of Science, the Chinese Biomedical Database (CBM), Chinese National Knowledge Infrastructure (CNKI) and the Wan Fang (Chinese) for the period up to March 2012. Finally, a total of 14 articles were identified, 10 with 1,657 cases and 6,971 controls for T869C polymorphism and 8 with 2,618 cases and 7,473 controls for C-509T polymorphism. The pooled ORs were performed for the allele contrasts, additive genetic model, dominant genetic model and recessive genetic model, respectively. Subgroup analysis was also performed by ethnicity. With respect to T869C and C-509T polymorphism, the combined results showed that there were no significant differences in genotype distribution between AD and control based on all studies. When stratifying for the race, there were also no statistically significant differences in genotype distribution between AD and controls. This meta-analysis did not provide an evidence of confirming association between the T869C and/or C-509T polymorphisms of the TGF-β1 gene and AD.     

The adaptive response of transforming growth factor-β2 and -βRII in the overloaded, regenerating and denervated muscles of rats

Using a muscle cell line and satellite cell cultures, it has been shown that transforming growth factor-β (TGF-β) has a powerful inhibitory effect on myoblast replication and differentiation. However, little work has been done on the possible role of TGF-β in adult muscle in vivo. Using Western blot and immunohistochemical analyses, we investigated normal distribution of TGF-β2 and TGF-βRII proteins between slow and fast-type muscles, and the adaptive response of these proteins in the mechanically overloaded muscles, in the regenerating muscles following bupivacaine injection and in the denervated muscle after section of sciatic nerve. Slight TGF-β2 immunoreactivity was detected both in slow- and fast-type muscles of mature rat. The amount of TGF-βRII protein was markedly greater in fast-type muscles. In the overloaded muscle, immunohistochemical analysis showed a marked increase in TGF-β2 immunoreactivity in the mononuclear cells (probably endothelial and perithelial or smooth muscle cells of endomysial capillaries) of the extracellular space at 3 and 6 days post surgery. Rapid increase of TGF-β2 protein and concomitant decrease of the receptor (TGF-βRII) were observed in the mechanically overloaded and regenerating muscles. On the other hand, denervation of slow- and fast-type muscles showed a rapid increase in TGF-β2 protein, but did not elicit a concomitant decrease of TGF-βRII. These results indicate that TGF-βRII is preferentially distributed in fast-type muscles. Furthermore, TGF-β2 may play an important role in muscle hypertrophy and regeneration by the usage of TGF-βRII. Received: 13 January 1999 / Revised: 22 April/15 June 1999 / Accepted: 17 June 1999     

Examination of glucose transporter-1, transforming growth factor-β and neuroglobin immunoreactivity in the orbitofrontal cortex in late-life depression

Aims: This study immunohistochemically examined the orbitofrontal cortex for three possible candidates in hypoxic/ischemic signaling: the cytokine transforming growth factor‐β, the glucose transporter‐1 and the neuron‐specific oxygen‐binding protein neuroglobin. Methods: Post‐mortem tissue from 20 depressed and 20 non‐depressed individuals was obtained and the expression of the three proteins was analyzed using image analysis software. Results: No significant changes were found in transforming growth factor‐β or neuroglobin in the orbitofrontal cortex between depressed and non‐depressed individuals. There was, however, a trend towards a reduction in glucose transporter‐1 in the depressed group. Conclusions: This study does not clearly support the hypothesis that hypoxic/ischemic processes are behind the pathological deficits in the frontal‐subcortical circuitry associated with depression and therefore does not provide evidence to support the ‘vascular depression’ hypothesis.     

Potential role of transforming growth factor-β1 in terminating the immune response in patients with Guillain-Barré syndrome

T-cell activation and proinflammatory cytokines seem to be important in promoting the disease activity in Guillain-Barré syndrome (GBS). Transforming growth factor-1 (TGF-1) is a multifunctional peptide with potent immunosuppressive activity, and can therefore be considered a putative disease-limiting cytokine. We determined levels of soluble TGF-1 in the serum of 12 patients with GBS in serial investigations during the course of the disease, in 12 patients with other non-inflammatory neurological diseases (OND), and in 12 healthy control subjects. Levels of biologically active and total TGF-1 were significantly increased in patients with GBS compared with patients with OND and healthy controls. During the course of GBS, levels of TGF-1 peaked in the plateau phase before onset of recovery. During the recovery phase levels of TGF-1 decreased but still exceeded significantly the levels in patients with OND and healthy controls. The differences were more marked with biologically active than with total TGF-1. The temporal relationship between increased serum levels of TGF-1 and the end of the progressive phase indicates that TGF-1 has a role in terminating the pathological immune response in GBS. These findings suggest that TGF-1 may be important in recovery from GBS.     

Expression of transforming growth factor-β1 and interleukin-1β mRNA in rat brain following transient forebrain ischemia

Transforming growth factor-1 (TGF-1) and interleukin-1 mRNA expression were studied in rat brains after 30 min of global ischemia by in situ hybridization. Ischemia was produced by four-vessel occlusion followed by different recirculation times ranging between 15 min and 7 days. TGF-1 mRNA could first be detected 3 days after ischemia in the hippocampus, in layers II/III of cortex, in the striatum and in parts of the ventral thalamus. At 7 days after recirculation a prominent increase in TGF-1 mRNA was observed in the CA1 sector of the hippocampus. Induction of interleukin-1 mRNA, however, was less marked and limited to the rostral striatum 3 and 7 days after ischemia. TGF-1 expression 7 days after ischemia correlated well with the histological localization of regions where neuronal degeneration and subsequent astrocytic and microglial activation had occurred. In adjacent brain sections, the distribution of TGF-1 mRNA after 7 days closely resembled that of the immunostaining pattern of activated microglia, indicating that at this time point TGF-1 mRNA was mainly produced by microglial cells. The late induction of TGF-1 mRNA after ischemia points to an involvement in the persistent glial response rather than the initial glial activation. The differential pattern of interleukin-1 mRNA induction indicates regional variations of cytokine production after ischemic brain lesions.Supported in part by a grant from the European Charcot Foundation for Multiple Sclerosis Research (to J.G.)     

The role of thrombospondin-1 and transforming growth factor-β after spinal cord injury in the rat

Spinal cord injury (SCI) continues to result in high morbidity and mortality throughout the world. An effective neuroprotective agent is still not available to counteract secondary damage caused by traumatic injury. Thrombospondin-1 (TSP-1) and transforming growth factor-β (TGF-β) have a role in angiogenesis, scar deposition, inflammation and may affect astrocyte phenotype and mobility. We investigated the role of TSP-1 and TGF-β in a model of spinal cord injury in rats. Forty female Sprague-Dawley rats were randomly divided into two equal groups: the experimental group was subject to SCI using an impactor and the sham-operated group was not subject to SCI. These animals were sacrificed at 12 h and 24 h after SCI for immunochemistry and Western blot analysis of the injured spinal segment for the expression of the TSP-1 and TGF-β proteins. We found that TSP-1 and TGF-β expression increased immediately after SCI in the injured segment. After 12 h, TSP-1 concentrations increased more rapidly and dramatically than TGF-β in the injured segment of the spinal cord. Elevations in TSP-1 and TGF-β concentrations persisted for 24 h after injury. These results show that elevated expression of TSP-1 and TGF-β can be detected in the injured segment of the spinal cord 12 and 24 h after injury. Thus, TSP-1 and TGF-β may have a role in SCI.     

Evaluation of serum transforming growth factor β1 and C-reactive protein levels in migraine patients

Background and purposeMigraine is a frequent form of headache. Although many mechanisms describing onset of migraine with and without visual aura have been suggested, the aetiology of migraine headaches is still not clear. Neurogenic inflammation may play a key role in the development of migraine headaches. We evaluated the discriminative power of serum levels of C-reactive protein (CRP) and transforming growth factor beta 1 (TGF-β1) in patients who presented to our clinic with migraine headaches with or without visual aura.Material and methodsWe designed a prospective case-control study of 51 patients with migraine (27 with migraine with aura and 24 with migraine without aura; all had headache) and compared them with 27 healthy subjects during the study period. Demographic and clinical characteristics recorded were age, sex, marital status, occupation, characteristics of headache, laboratory values, and serum CRP and TGF-β1 levels. Statistical analyses used Student t-test, the χ² test, and ANOVA followed by the post-hoc Bonferroni test for multiple comparisons. Receiver operator characteristic (ROC)-curve analysis for CRP and TGF-β1 was also conducted.ResultsThere was no difference between the groups in terms of demographic characteristics, marital status, and socioeconomic status. Statistically, white blood cell levels, serum glucose levels, triglyceride levels, high-density lipoprotein levels, and serum CRP and TGF-β1 were significantly higher in patients with migraine (p < 0.05). The ROC curve results in this study identified that CRP and TGF-β1 may discriminate patients who have different types of migraine headache.ConclusionsThis study suggests that serum CRP and TGF-β1 levels may be diagnostic factors to differentiate migraine patients with and without aura. These findings show that neurogenic inflammation may have a role in the aetiology of migraines.     

The transforming growth factor-β receptor genes and the risk of intracranial aneurysms

Background Mutations in the receptor genes of the transforming growth factor β pathway, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysms, while genetic variants in TGFBR1 and TGFBR2 are associated with abdominal aortic aneurysms. The transforming growth factor-β pathway may be involved in aneurysm development in general. Aims To analyze whether genetics variants in TGFBR1 and TGFBR2 are also involved in the pathogenesis of intracranial aneurysms. Methods Using tag single nucleotide polymorphisms, we analyzed all common genetic variants in TGFBR1 (five single nucleotide polymorphisms) and TGFBR2 (26 single nucleotide polymorphisms) in a Dutch intracranial aneurysm case-control population approach using a two-stage genotyping approach. Results In stage 1, on analyzing 481 patients and 648 controls, two of the five single nucleotide polymorphisms in TGFBR1 were associated with intracranial aneurysm with P<0·10. In an independent cohort of 310 intracranial aneurysm patients and 376 controls, a predominance of the allele of the two single nucleotide polymorphisms found more frequently in patients in stage 1 was also observed in patients of stage 2 but the associations were not statistically significant. On combined analyses of both stages, there was a statistically significant association of both single nucleotide polymorphisms with intracranial aneurysm (single nucleotide polymorphism rs1626340, odds ratio 1·24, 95% confidence intervals 1·05-1·46, P=0·01; single nucleotide polymorphism rs10819634, odds ratio 1·23, 95% confidence intervals 1·03-1·46, P=0·02) but these associations did not hold after multiple testing correction (i.e., P<0·0016, 0·05/31). Also, no differences in the single nucleotide polymorphism frequency were observed for TGFBR2 between patients and controls. Conclusions We found no evidence for TGFBR1 and TGFBR2 as susceptibility genes for intracranial aneurysm in the Dutch population.     

Expression of basic fibroblast growth factor,nerve growth factor,platelet-derived growth factor and transforming growth factor-β in human brain abscess

We correlated the histopathological findings of six human brain abscesses with the expression of basic fibroblast growth factor (bFGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF). The clinical courses ranged from 1 month to 1 year and viridans streptoccus was the major pathogen. In early abscesses, we demonstrated strong bFGF and moderate NGF and PDGF immunoreactivities in neutrophils and monocytes/macrophages infiltrating the abscess wall and in the fibrin layer lining the abscess center. In the subacute cases, growth of capillaries and fibroblasts into the fibrin layer and deposition of collagen resulted in the formation of a mesodermal layer between the abscess center and the outer gliotic layer. The proliferative non-neural cells (endothelial cells, fibroblasts and glial cells) expressed mild to strong bFGF, NGF and PDGF immunoreactivities, while strong TGF staining was seen in the extracellular matrix. A loss of growth factor expression and increased fibrosis was seen in the chronic case. These findings suggest that bFGF, NGF, PDGF and TGF produced by the continued influx of leukocytes and by the proliferating non-neural cells may mediate various steps of defense mechanisms and wound healing such as angiogenesis, fibrogenesis and gliosis.Supported by NSC-82-0115-B-006-127 from the National Science Council, Republic of China     

The correlation of plasma Aβ42 levels, depressive symptoms, and cognitive function in the Korean elderly

Objectives

This study aims to investigate whether plasma amyloid beta 1-42 (Aβ42) levels are associated with depressive symptoms and/or cognitive function in community dwelling elderly.

Methods

Subjects were 123 participants of a population-based project designed to screen community dwelling elderly older than 65 years old in Gangwon Province, Korea, for the early detection of depression and dementia. Symptoms of depression were assessed using the SGDS-K (Short Geriatric Depression Scale-Korean version), and the MMSE-KC (Mini-Mental State Examination-Korean version) was used to assess cognitive function. Plasma Aβ42 levels were measured with the human amyloid beta ELISA Kit.

Results

The elderly with depressive symptoms (SGDS-K score ≥ 8) had higher plasma Aβ42 levels than those without depressive symptoms (SGDS-K score < 8) (p < 0.1). Plasma Aβ42 levels were positively correlated with SGDS-K scores (p < 0.05). However, MMSE-KC scores were inversely associated with plasma Aβ42 levels (p < 0.01). Plasma β42 levels were also associated with MMSE-KC (F = 8.07, p < 0.01) and SGDS-K (F = 4.53, p < 0.05) by generalized linear model (GLM) with controlling age, sex and education.

Conclusion

Plasma Aβ42 levels were associated with depressive symptoms and cognitive function in community dwelling elderly. The present study supports the possibility that plasma Aβ may be involved in the development of late onset depression.     

Transforming growth factor-β1 in the cerebrospinal fluid of patients with distinct neurodegenerative diseases

A chronic inflammatory condition may underlie neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). For example, both PD and AD patients show an increase in transforming growth factor-β1 (TGF-β1) levels in their cerebrospinal fluid (CSF). TGF-β1 is a cytokine that inhibits inflammation. In the present study, using an enzyme-linked immunosorbent assay, we tested the hypothesis that the level of TGF-β1 in the CSF of patients with amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD), or multiple system atrophy-cerebellar subtype (MSA-C) would be elevated compared with that of normal controls. We found that TGF-β1 levels in the CSF were not significantly different between these patients and normal controls. Our data suggest that the level of TGF-β1 in the CSF is an unreliable biomarker of ALS, SCD, and MSA-C.     

Detection of two transforming growth factor-β-related morphogens,bone morphogenetic proteins-4 and-5, in RNA of multiple sclerosis and Creutzfeldt-Jakob disease lesions

The bone morphogenetic proteins (BMPs) constitute a novel subfamily of the transforming growth factor type (TGF-) supergene family. Here we demonstrate, using polymerase chain reaction (PCR) BMP-4 and BMP-5 messages in RNA isolated from multiple sclerosis (MS) plaque tissue. This is the first demonstration of BMP expression in an inflammatory lesion in general, and in MS in particular. However, BMP-4 and BMP-5 messages could be detected in RNA isolated from a Morbus Creutzfeldt-Jakob (CJD) lesion. Even in normal brain, RNA expression of BMP-4, but not that of BMP-5, was detected. Therefore, BMP-5 gene expression seems to be associated with MS and CJD lesions, whereas the BMP-4 gene appears to be constitutively expressed in the human brain. As TGF-s and BMPs are regulators of regenerative processes and contribute to regulation of chemoattraction and local immunoreactivity, BMP-4 and BMP-5 might be involved in aspects of MS lesion formation unknown so far. PCR analysis of human cell lines demonstrate BMP-4 and BMP-5 expression in leukocytic cells, suggesting that infiltrating leukocytes contribute at least in part to BMP-4 and BMP-5 mRNAs of the MS plaque.     

Mutations affecting synaptic levels of neurexin-1β in autism and mental retardation

The identification of mutations in genes encoding proteins of the synaptic neurexin-neuroligin pathway in different neurodevelopmental disorders, including autism and mental retardation, has suggested the presence of a shared underlying mechanism. A few mutations have been described so far and for most of them the biological consequences are unknown. To further explore the role of the NRXN1β gene in neurodevelopmental disorders, we have sequenced the coding exons of the gene in 86 cases with autism and mental retardation and 200 controls and performed expression analysis of DNA variants identified in patients. We report the identification of four novel independent mutations that affect nearby positions in two regions of the gene/protein: i) sequences important for protein translation initiation, c.-3G>T within the Kozak sequence, and c.3G>T (p.Met1), at the initiation codon; and ii) the juxtamembrane region of the extracellular domain, p.Arg375Gln and p.Gly378Ser. These mutations cosegregate with different psychiatric disorders other than autism and mental retardation, such as psychosis and attention-deficit/hyperactivity disorder. We provide experimental evidence for the use of an alternative translation initiation codon for c.-3G>T and p.Met1 mutations and reduced synaptic levels of neurexin-1β protein resulting from p.Met1 and p.Arg375Gln. The data reported here support a role for synaptic defects of neurexin-1β in neurodevelopmental disorders.     

Association between morningness–eveningness and the severity of compulsive Internet use: the moderating role of gender and parenting style

BackgroundEveningness and Internet addiction are major concerns in adolescence and young adulthood. We investigated the relationship between morningness–eveningness and compulsive Internet use in young adults and explored the moderating effects of perceived parenting styles and family support on such relationships.MethodsThe participants consisted of 2731 incoming college students (men, 52.4%; mean age, 19.4 ± 3.6 years) from a National University in Taiwan. Each participant completed the questionnaires, which included the Morningness–Eveningness Scale (MES), the Yale-Brown Obsessive Compulsive Scale modified for Internet use (YBOCS-IU), the Parental Bonding Instrument for parenting style, the Family Adaptation, Partnership, Growth, Affection, and Resolve questionnaire (APGAR) for perceived family support, and the Adult Self-Report Inventory-4 (ASRI-4) for psychopathology. The morning (n = 459), intermediate (n = 1878), and evening (n = 394) groups were operationally defined by the MES t scores.ResultsThe results showed that eveningness was associated with greater weekend sleep compensation, increased compulsive Internet use, more anxiety, poorer parenting styles, and less family support; additionally, the most associated variables for increased compulsive Internet use were the tendency of eveningness, male gender, more anxiety symptoms, less maternal affection/care, and a lower level of perceived family support. The negative association between the morning type and compulsive Internet use severity escalated with increased maternal affection/care and decreased with increased perceived family support. The positive association between the evening type and compulsive Internet use severity declined with increased maternal protection. However, the father’s parenting style did not influence the relationship between morningness–eveningness and compulsive Internet use severity.ConclusionsOur findings imply that sleep schedule and the parental and family process should be part of specific measures for prevention and intervention of compulsive Internet use.     

Association of transforming growth factor-β1 gene C509T,G800A and T869C polymorphisms with intracerebral hemorrhage in North Indian Population: a case–control study

Transforming growth factor-β1 (TGF-β1) is a multifunctional pro-inflammatory cytokine involved in inflammation and pathogenesis of cerebrovascular disease. As per our knowledge, there is no published study investigating the association between variations within the TGF-β1 gene polymorphisms and risk of intracerebral hemorrhage (ICH). The aim of this study was to investigate the association of the TGF-β1 gene (C509T, G800A and T869C) polymorphisms, and their haplotypes with the risk of ICH in North Indian population. 100 ICH patients and 100 age- and sex-matched controls were studied. Genotyping was performed using SNaPshot method. Conditional logistic regression analysis was used to calculate the strength of association between TGF-β1 gene polymorphisms and risk of ICH. Hypertension, diabetes, dyslipidemia, low socioeconomic status, smoking, physical activity were found to be associated with the risk of ICH. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy–Weinberg Equilibrium (HWE) in the ICH and control group. Adjusted conditional logistic regression analysis showed an independent association of TGF-β1 G800A (OR 9.07; 95 % CI 2.3–35.6; P = 0.002) and T869C (OR 5.1; 95 % CI 1.9–13.2; P = 0.001) with the risk of ICH under dominant model. Haplotype analysis showed that C509-G800-C869 and C509-A800-C869 haplotypes were significantly associated with the increased risk of ICH. C509T and T869C were in strong linkage disequilibrium (D’ = 0.53, r ² = 0.23). Our results suggest that TGF-β1 (G800A, T869C) gene polymorphisms and their haplotypes are significantly associated with the risk of ICH in North Indian population. Further prospective studies with large sample size are required for independent validation. Our findings could be helpful in identifying individuals at increased risk for developing ICH.