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Background: NRG1 and its receptor ErbB4 are schizophrenia susceptibility genes. Results: NRG1 induced the up-regulation of EAAC1 with an increase in glutamate uptake. Conclusion: NRG1/ErbB4 signaling influences glutamate uptake by increasing the EAAC1 protein level. Significance: These results contribute to understanding of a possible mechanism of NRG1/ErbB4 signaling that may be linked to the neural circuitry disruption in schizophrenia.

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.

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.

BackgroundThere 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.ResultsThe 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.ConclusionThe 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.