Neuregulin 1 Controls Glutamate Uptake by Up-regulating Excitatory Amino Acid Carrier 1 (EAAC1).

Neuregulin 1 (NRG1) is a trophic factor that is thought to have important roles in the regulating brain circuitry. Recent studies suggest that NRG1 regulates synaptic transmission, although the precise mechanisms remain unknown. Here we report that NRG1 influences glutamate uptake by increasing the protein level of excitatory amino acid carrier (EAAC1). Our data indicate that NRG1 induced the up-regulation of EAAC1 in primary cortical neurons with an increase in glutamate uptake. These in vitro results were corroborated in the prefrontal cortex (PFC) of mice given NRG1. The stimulatory effect of NRG1 was blocked by inhibition of the NRG1 receptor ErbB4. The suppressed expression of ErbB4 by siRNA led to a decrease in the expression of EAAC1. In addition, the ablation of ErbB4 in parvalbumin (PV)-positive neurons in PV-ErbB4(-/-) mice suppressed EAAC1 expression. Taken together, our results show that NRG1 signaling through ErbB4 modulates EAAC1. These findings link proposed effectors in schizophrenia: NRG1/ErbB4 signaling perturbation, EAAC1 deficit, and neurotransmission dysfunction.

Down-regulation of microglial activity attenuates axotomized nigral dopaminergic neuronal cell loss.

BACKGROUND: There is growing evidence that inflammatory processes of activated microglia could play an important role in the progression of nerve cell damage in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease which harbor features of chronic microglial activation, though the precise mechanism is unknown. In this study, we presented in vivo and ex vivo experimental evidences indicating that activated microglia could exacerbate the survival of axotomized dopaminergic neurons and that appropriate inactivation of microglia could be neuroprotective. RESULTS: The transection of medial forebrain bundle (MFB) of a rat induced loss of dopaminergic neurons in a time-dependent manner and accompanied with microglial activation. Along with microglial activation, production of reactive oxygen species (ROS) was upregulated and TH/OX6/hydroethidine triple-immunofluorescence showed that the microglia mainly produced ROS. When the activated microglial cells that were isolated from the substantia nigra of the MFB axotomized animal, were transplanted into the substantia nigra of which MFB had been transected at 7 days ago, the survival rate of axotomized dopaminergic neurons was significantly reduced as compared with sham control. Meanwhile, when the microglial activation was attenuated by administration of tuftsin fragment 1-3 (microglia inhibitory factor) into the lateral ventricle using mini-osmotic pump, the survival rate of axotomized dopaminergic neurons was increased. CONCLUSION: The present study suggests that activated microglia could actively produce and secrete unfavorable toxic substances, such as ROS, which could accelerate dopaminergic neuronal cell loss. So, well-controlled blockade of microglial activation might be neuroprotective in some neuropathological conditions.

Neuregulin-1 exerts protective effects against neurotoxicities induced by C-terminal fragments of APP via ErbB4 receptor.

Neuregulin-1 (NRG1) plays important roles in the development and plasticity of the brain, and it is also reported to have potent neuroprotective properties. We previously reported that NRG1 has neuroprotective actions against Swedish amyloid precursor protein-induced neurotoxicity. In addition to the amyloid beta peptide, other metabolites of amyloid precursor protein (APP) such as the C-terminal fragments of APP (APP-CTs) have been reported to possess cytotoxic effects in neuronal cells. In this study, we investigated whether NRG1 exerts neuroprotective effects against APP-CTs and attempted to determine its neuroprotective mechanisms. NRG1 attenuated the neurotoxicities induced by the expression of APP-CTs in neuronal cells. NRG1 also reduced the accumulation of reactive oxygen species and attenuated mitochondrial membrane potential loss induced by APP-CTs. In addition, NRG1 upregulated the expression of the anti-apoptotic protein Bcl-2. This effect was blocked by the inhibition of ErbB4, a key NRG1 receptor. Taken together, these results demonstrate the neuroprotective potential of NRG1 in Alzheimer's disease.

Tumor-mediated down-regulation of MHC class II in DC development is attributable to the epigenetic control of the CIITA type I promoter.

In patients with cancer, DC express significantly lower amounts of MHC class II compared with those of normal individuals. However, the underlying mechanisms for this have not yet been fully defined. In the present study, we found that IL-10 plays a major role in the tumor-conditioned medium (TCM)-mediated decrease of MHC class II expression on BM-derived DC. IL-10 inhibited the expression of type I CIITA during DC differentiation. GM-CSF-mediated histone (H3 and H4) acetylation at the type I promoter (pI) locus of the CIITA gene was markedly increased during DC differentiation and this increase was blocked by IL-10. We also found that STAT5 bound to the CIITA pI locus during DC differentiation, and the binding was markedly attenuated by TCM or IL-10. Altogether, these findings suggest that (i) the down-regulation of MHC class II in tumor microenvironments is most likely attributable to IL-10 in the TCM and (ii) IL-10-mediated MHC class II down-regulation results from the inhibition of type I CIITA expression. This inhibition is most likely due to blocking of the STAT5-associated epigenetic modifications of the CIITA pI locus during the entire period of DC differentiation from BM cells, as opposed to a simple inhibition of MHC class II expression at the DC stage.

Role of activating transcription factor 3 in ischemic penumbra region following transient middle cerebral artery occlusion and reperfusion injury.

The activating transcription factor 3 (ATF3) is expressed by various types of cellular insults. It has been suggested to serve diverse functions in both cellular survival and death signal cascades, but the exact role of ATF3 in brain ischemia is little known so far. Thus, the authors examined the expression pattern of ATF3 following middle cerebral artery occlusion (MCAO) and reperfusion injury. At 1-2 days after MCAO and reperfusion injury, numerous number of ATF3-immunoreacitive (-ir) nuclei was observed in the ipsilateral peri-infarct cortex, but declined rapidly at 3 days. Almost all ATF3-ir nuclei were co-localized with NeuN-ir neurons. Neither GFAP- nor OX42-ir neuroglia were co-localized with ATF3. Double labeling of Fluoro-Jade B with ATF3 showed that ATF3-ir nuclei mismatched with Fluoro-Jade B-ir neurons. To further examine the role of ATF3 in ischemic peri-infarct regions, double immunofluorescent labeling of ATF3/caspase 3, ATF3/Bcl-xl, and ATF3/HSP27 was conducted. Semiquantitive estimation showed that about 15% of ATF3-ir neurons also expressed caspase 3. However, about only 0.4% and 2.6% of ATF3-ir neurons were double-stained with Bcl-xl and Hsp27, respectively. Consequently, it would be suggested that ATF3 seem to play an important role in caspase-dependent neuronal apoptotic signal transduction pathways caused by focal cerebral ischemia and reperfusion injury.

Expression of ErbB4 in the neurons of Alzheimer's disease brain and APP/PS1 mice, a model of Alzheimer's disease.

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.

Expression of ErbB4 in the apoptotic neurons of Alzheimer's disease brain.

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.