Neuregulin-1 (NRG1) signaling participates in the synaptic plasticity, maintenance or regulation of adult brain. Although ErbB4, a key NRG1 receptor, is expressed in multiple regions in the adult animal brain, little is known about its localization in Alzheimer's disease (AD) brains. We previously reported that ErbB4 immunoreactivity showed regional difference in the hippocampus of age-matched control. In the present paper, immunohistochemical characterization of the distribution of ErbB4 receptor in the hippocampus relative to pathology staging were performed in age-matched control (Braak stage 0, n=6) and AD (Braak stage I/V, n=10). Here, we found that ErbB4 immunoreactivity was significantly increased in apoptotic hippocampal pyramidal neurons in the brains of AD patients, compared to those of age-matched control subjects. In AD brains, ErbB4 immunoreactivity was demonstrated to colocalize with the apoptotic signal Bax in apoptotic hippocampal pyramidal neurons. These results suggest that up-regulation of ErbB4 immunoreactivity in apoptotic neuron may involve in the progression of pathology of AD.
Adult ; Alzheimer Disease ; Animals ; Apoptosis ; Brain ; Hippocampus ; Humans ; Neuregulin-1 ; Neurons ; Plastics ; Up-Regulation

PURPOSE: Heregulin is a natural ligand for erbB3 and erbB4. However, very little is known about their roles in the gastric cancer. This retrospective study was performed to evaluate the frequencies of heregulin and erbB family protein expression and to compare their expressions with clinicopathologic parameters. MATERIALS AND METHODS: Immunohistochemical expressions of heregulin and erbB family proteins were examined with tissue micro-array slides. A total of 251 gastric adenocarcinomas were classified as early cancers and advanced cancers and as having and not having lymph node metastases. RESULTS: The positive rates of the heregulin, erbB1, erbB2, erbB3, and erbB4 protein stainings were 64%, 68%, 6%, 88%, and 76%, respectively. Intestinal type gastric adenocarcinomas showed higher expression of heregulin, erbB2, erbB3, and erbB4 proteins. Heregulin and erbB4 proteins showed lower expressions in advanced gastric carcinomas. However, erbB2 protein showed higher expression in advanced gastric carcinomas. The protein expressions of heregulin and erbB family proteins showed no relationship with survival rate. Co-expression groups of heregulin and erbB3 proteins or heregulin and erbB4 proteins showed higher expressions in intestinal type adenocarcinomas and early gastric carcinomas. CONCLUSION: Heregulin, erbB3, and erbB4 proteins may play a role in the early stage of adenocarcinomas.
Adenocarcinoma* ; Humans ; Immunohistochemistry ; Lymph Nodes ; Neoplasm Metastasis ; Neuregulin-1* ; Retrospective Studies ; Stomach Neoplasms ; Survival Rate

Neuregulin-1 (NRG1) has been shown to be able to protect against focal cerebral ischemia. The aim of the present study was to investigate the neuroprotective effect of NRG1 in primary hippocampal neurons and its underlying mechanism. Our data showed oxygen-glucose deprivation (OGD)-induced cytotoxicity and overexpression of ErbB4 in primary hippocampal neurons. Moreover, pretreatment with NRG1 could inhibit OGD-induced overexpression of ErbB4. In addition, NRG1 significantly attenuated neuronal death induced by OGD. The neuroprotective effect of NRG1 was blocked in ischemic neurons after pretreatment with AG1478, an inhibitor of ErbB4, but not after pretreatment with AG879, an inhibitor of ErbB2. These results indicate an important role of ErbB4 in NRG1-mediated neuroprotection, suggesting that endogenous ErbB4 might serve as a valuable therapeutic target for treating global cerebral ischemia.]]>
Anoxia ; Brain ; Brain Ischemia ; Cell Death ; Cognition ; Hippocampus ; Ischemia ; Neuregulin-1 ; Neurons ; Neuroprotection ; Neuroprotective Agents

Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Although ErbB4, a key NRG1 receptor, is expressed in multiple regions in the adult animal brain, little is known about its expression in aged human brain. We show that ErbB4 immunoreactivity was shown regional difference in the hippocampus of age-matched control and that the distribution of these molecules was altered in Alzheimer's disease (AD) brains. Immunohistochemical characterization of the distribution of ErbB4 receptor in the hippocampus relative to pathology staging were performed in age-matched control (Braak stage I/II, n=5), early AD (Braak stage III/IV, n=5) and advanced AD(Braak stage V/VI, n=10). The intensity of ErbB4 immunoreactivity was higher in neurons of the CA2 than that in CA1 or CA3 in the age-matched control. Particularly, in the early AD, ErbB4 immunoreactivity was significantly increased in the apoptotic cells of the CA2 field. In the advanced AD, ErbB4 immunostaining was more intense in the apoptotic cell of the CA2 field. In the dentate gyrus (DG), ErbB4-positive granular cell density was gradually increased in proportion to the progression of pathology of AD brains. We have also found that ErbB4 immunostaining was increased in the nucleus, suggesting that the presenilin-dependent cleavage of ErbB4 generates the soluble ErbB4 ICD (intracellular domain) that translocalized to the nucleus. Together, these results provide the immunohistochemical analysis of ErbB4 receptor in the human hippocampus staged by the progression of pathology of AD.
Adult ; Aged ; Alzheimer Disease ; Animals ; Apoptosis ; Brain ; Cell Count ; Dentate Gyrus ; Hippocampus ; Humans ; Neuregulin-1 ; Neurons

Neuregulin-1 (NRG1) plays important roles in the development and plasticity of the brain, and has also been reported to exhibit potent neuroprotective properties. Although ErbB4, a key NRG1 receptor, is expressed in multiple regions in the adult animal brain, little is known about its role in Alzheimer's disease (AD). AD is characterized by progressive impairment of cognition and behavioral disturbance that strongly correlate with degeneration and death of neurons in the cerebral cortex and limbic brain areas, such as the hippocampus and the amygdala. Here, we show that the ErbB4 and phospho-ErbB4 immunoreactivities were higher intensity in the neurons of the CA1-2 transitional field of AD brains as compared to age-matched controls. Also, ErbB4 expression was increased in the neurons of the cortico medial nucleus amygdala, human basal forebrain and superior frontal gyrus of AD brains. In cerebral cortex and hippocampus of amyloid precursor protein/presenilin 1 double transgenic mice, ErbB4 immunoreactivity significantly increased in comparison to age-matched wild type control. These results suggest that up-regulating of ErbB4 immunoreactivity may involve in the progression of pathology of AD.
Adult ; Alzheimer Disease ; Amygdala ; Amyloid ; Animals ; Brain ; Cerebral Cortex ; Cognition ; Hippocampus ; Humans ; Mice ; Mice, Transgenic ; Neuregulin-1 ; Neurons ; Plastics ; Prosencephalon

Neuregulin 1 (NRG1) is associated with the pathogenesis of schizophrenia through controlling activation and signaling of neurotransmitter receptors. Influence to schizophrenia development by the NRG1 gene may differ in individuals, and genetic polymorphism is one of the factors affecting their differences. Association between three single nucleotide polymorphisms (SNPs) (rs7014762, -1174 A/T; rs11998176, -788 A/T; rs3924999, Arg253Gln) of NRG1 and the development of schizophrenia was analyzed in 221 schizophrneia and 359 control subjects. Polymerase chain reaction and direct sequencing were performed to obtain genotype data of NRG1 SNPs of the subjects. In analysis of genetic data, multiple logistic regression models (codominant1, codominant2, dominant, recessive, and log-additive model) were applied. SNPStats and SPSS 18.0 were used to calculate odds ratio (OR), 95% confidence interval (CI), and p-value of each model. The genotype distributions of rs3924999 were associated with schizophrenia development (OR=0.67, 95% CI=0.47-0.95, p=0.022 in the dominant model and OR=0.69, 95% CI=0.51-0.93, p=0.013 in the log-addtive model) and allelic distributions also showed significant association (OR=0.70, 95% CI=0.52-0.93, p=0.014). The results suggest that rs3924999 of the NRG1 gene may be associated with schizophrenia susceptibility.
Genotype ; Logistic Models ; Neuregulin-1 ; Odds Ratio ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Receptors, Neurotransmitter ; Schizophrenia

Objective: To investigate the effect of neuregulin-1(NRG-1) on cardiac glucose metabolism in Sprague Dawley (SD) rats with experimental myocardial infarction (MI). Methods: Adult male SD rats were randomly divided into three groups: the sham-operated group, MI group, and MI+NRG1 group. The rat MI model was established via ligation of the left anterior descending coronary artery. Two weeks after operation, echocardiography was performed, MI rats with left ventricular ejection fraction (LVEF) between 0.3-0.5 were selected and randomly assigned to MI group and MI+NRG-1 group. Rats in MI+NRG-1 group were treated with recombinant human NRG-1β (100 μg/kg) via tail vein at 2 weeks after operation (twice per week for 6 weeks); while rats in sham-operated group and MI group received equal volume of physiological saline. By the end of administration, echocardiography and small animal positron emission tomography (PET) were performed to detect cardiac function and myocardial glucose uptake. Myocardial morphology and collagen volume fraction, cardiomyocyte apoptosis and reactive oxygen species (ROS) production were evaluated by histopathologic analysis. Myocardial pyruvate dehydrogenase (PDH) and citrate synthase (CS) activity, as well as ATP production were detected by commercial kits. The mRNA and protein expression levels of NRG-1, p-ErbB4, and key factors involved in glucose metabolism (including Glut-4, HK2, PDK4, PDH, CS) were detected by quantitative real-time PCR (qRT-PCR) and Western blot assay, respectively. Results: With the MI model successfully established, the left ventricular ejection fraction(LVEF) and left ventricular shortening fraction(LVFS) were significantly lower in MI group and MI+NRG-1 group than that in sham group (both P<0.01), while there was no significant difference between MI group and MI+NRG-1 group(all P>0.05). After 6 weeks of NRG-1β intervention, the LVEF and LVFS were significantly higher in MI+NRG-1 group than in MI group (both P<0.01). By the end of experiment, PET imaging showed that the mean standardized uptake value (SUVmean) were lower in MI+NRG-1 group than in the sham group (4.06±0.28 vs. 5.18±0.37, P<0.01), while significantly higher than that in MI group (4.06±0.28 vs.2.86±0.49, P<0.01). Histopathological analysis showed that compared with MI group, rats in MI+NRG-1 group exhibited significantly decreased left ventricle collagen volume fraction ((7.83±1.24) % vs. (18.31±3.58) %, P<0.01), cardiomyocyte apoptosis((37.98±4.26)% vs. (67.04±5.38)%, P<0.01), and DHE fluorescence intensity(0.057 28±0.007 06 vs. 0.076 94±0.008 46, P<0.01), indicating that NRG-1β could reduce ROS production. PDH activity, CS activity, and ATP production were significantly higher in MI+NRG-1 group than in MI group (all P<0.05). qRT-PCR demonstrated an upregulated Glut-4, HK2 and CS, but downregulated PDK4 mRNA expression in MI+NRG-1 group compared with MI group (all P<0.01). Western blot assay showed significantly higher protein expression of NRG-1, p-ErbB4, Glut-4, HK2, PDH, CS in MI+NRG-1 group than in MI group (all P<0.01). Conclusion: NRG-1 could improve glucose uptake and utilization in myocardium by activating phosphorylation of myocardial ErbB4 receptor in MI rats, thus providing a therapeutic option for improving energy metabolism after MI.
Animals ; Glucose ; Male ; Myocardial Infarction/drug therapy* ; Myocardium ; Neuregulin-1 ; Rats ; Rats, Sprague-Dawley ; Stroke Volume ; Ventricular Function, Left

BACKGROUNDMesenchymal stem cells are a promising cell type for cell transplantation in myocardial infarction. Type I neuregulins-1, also known as heregulin, can promote the survival of cardiomyocytes and stimulate angiogenesis. The purpose of this study was to investigate the expression of heregulin and ErbB receptors in mesenchymal stem cells, then further detect the secretion of heregulin and the changes in expression of heregulin and ErbB receptors under conditions of serum deprivation and hypoxia.

METHODSMesenchymal stem cells isolated from bone marrow of 180 g male Sprague-Dawley rats were cultured. Passage 3 cells were detected experimentally by regular reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real time PCR and Western blotting.

RESULTSHeregulin and ErbB receptors were expressed in mesenchymal stem cells, and all three ErbB receptors mRNA expressions were significantly down-regulated by serum deprivation and hypoxia, but serum deprivation and hypoxia significantly increased the protein expression of heregulin. Serum deprivation and hypoxia more than 12 hours could induce the secretion of heregulin.

CONCLUSIONSMesenchymal stem cells can express all three ErbB receptors and heregulin. Serum deprivation and hypoxia decrease the mRNA expression of ErbB receptors, increase the expression of heregulin, and activate the secretion of heregulin.

Animals ; Cell Hypoxia ; Cells, Cultured ; Male ; Mesenchymal Stromal Cells ; chemistry ; metabolism ; Neuregulin-1 ; analysis ; genetics ; Oncogene Proteins v-erbB ; analysis ; genetics ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley

OBJECTIVES: The authors recently found a suggestive evidence of linkage of chromosome 8p21-12 to schizophrenia in Korean multiplex families. Neuregulin 1 (NRG1) was identified in this locus as a positional and functional candidate gene for schizophrenia, through several independent studies with European and Chinese populations. The purpose of this study is to determine whether NRG1 is associated with schizophrenia in Korean population. METHODS: Three SNPs (SNP8NRG221533, SNP8NRG241930, SNP8NRG243177) and two microsatellites markers (478B14-848, 420M9-1395) located at the 5' end of NRG1 were genotyped for 242 unrelated schizophrenia patients and the same number of normal controls. Genetic association was tested by chi2-test (df=1). Not only for the whole patients group but also for a subgroup of patients with auditory hallucination. This subtype showed stronger linkage with chromosome 8p12 in the prior study of the authors with multiplex families. RESULTS: G allele of SNP8NRG241930 was significantly in excess in the subgroup of patients with auditory hallucination compared to the control group (p=0.03, OR=1.76). We also found that 3 SNPs haplotype TTC (p=0.04, OR=0.58) and five markers haplotype TTC53 (p=0.01, OR=0.49) were associated with schziophrenia with a protective effect. Three SNPs haplotype CGT which is a part of the at-risk haplotype of the Icelandic schizophrenia families was found in excess in the patients group but no significant association was observed. CONCLUSION: NRG1 might either play a role in the predisposition to schizophrenia or be in linkage disequilibrium with a causal locus of this illness.
Alleles ; Asian Continental Ancestry Group ; Genetic Variation* ; Hallucinations ; Haplotypes ; Humans ; Iceland ; Linkage Disequilibrium ; Microsatellite Repeats ; Neuregulin-1* ; Polymorphism, Single Nucleotide ; Schizophrenia*

BACKGROUND AND OBJECTIVES: Schwann-like (SC-like) cells induced from adipose-derived stem cells (ASCs) may be one of the ideal alternative cell sources for obtaining Schwann cells (SCs). They can be used for treating peripheral nerve injuries. Co-culture with SCs or exposure to glial growth factors are commonly used for differentiation of ASCs to SC-like cells. However, the effect of initial cell density as an inductive factor on the differentiation potential of ASCs into the SC-like cells has not been yet investigated. METHODS AND RESULTS: ASCs were harvested from rat and characterized. The cells were seeded into the culture flasks at three different initial cell densities i.e. 2×10³, 4×10³ and 8×10³ cells/cm² an overnight and differentiated toward SC-like cells using glial growth factors. After two weeks, the differentiation rate of ASCs to SC-like cells at different densities was assessed by immunofluorescence, fluorescence-activated cell sorting analysis and real time RT-PCR. Expression of the typical SCs markers, S-100 proteins and glial fibrillary acidic protein (GFAP) protein, was observed in all cell densities groups although the number of S100-positive and GFAP-positive cells, and the expression of p75(NTR) mRNA, another SC marker, were significantly higher at the density of 8×10³ cells/cm² when compared with the other cell densities groups (p<0.001). CONCLUSIONS: The results suggest that the higher differentiation rate of ASCs to SC-like cells can be obtained at initial cell density of 8×10³ cells/cm², possibly via increased cell-cell interaction and cell density-dependent influence of glial growth factors.
Animals ; Cell Count* ; Coculture Techniques ; Flow Cytometry ; Fluorescent Antibody Technique ; Glial Fibrillary Acidic Protein ; Neuregulin-1 ; Peripheral Nerve Injuries ; Rats* ; RNA, Messenger ; S100 Proteins ; Schwann Cells ; Stem Cells*