Oral Sessions

Oral Sessions グリア、ミエリン、神経免疫

2O3-1 Anti-MOG autoantibody induces morphological changes in oligodendrocytes Yoshio Bando，Shigetaka Yoshida Dept Functional Anat. and Neurosci., Asahikawa Med Univ Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Demyelination and axonal damage are responsible for neurological deficits in MS. It is well known that anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies are present in MS patients. However, anti-MOG autoantibodies-mediated demyelination has not been well understood. In the current study, we investigated the effect of anti-MOG autoantibody on oligodendrocytes in vitro. Differentiated oligodendrocytes induced by treatment of triiodothyronine were used in the current study. These cells were also treated with either vehicle or anti-MOG autoantibody for 24hr. TUNEL staining showed treatment of anti-MOG autoantibody itself did not induce oligodendroglial cell death. However, immunocytochemistry demonstrated that cell enlargement stained with anti-myelin basic protein (MBP) antibody was observed in anti-MOG autoantibody-treated oligodendrocytes. In addition, immunoblot analysis displayed an increased level of MBP expression in anti-MOG autoantibody-treated oligodendrocytes, compared with vehicle-treated oligodendrocytes. Moreover, Fyn, which is essential for promoting accelerated MBP expression, was also elevated in anti-MOG autoantibody-treated oligodendrocytes. These results indicate that anti-MOG autoantibody induces abnormalities of MBP expression followed by abnormal morphological changes in oligodendrocytes.		2O3-2 Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica Kana Harada，Yuki Fujita，Toshihide Yamashita Dept of Molecular Neuroscience, Graduate School of Medicine, Osaka University Neuromyelitis optica (NMO) is an autoimmune disease associated with NMO-IgG, an antibody that selectively binds to the aquaporin 4 water channel. Here, we developed a localized NMO model by injecting NMO-IgG into the spinal cord, and assessed the efficacy of treating its NMO-like symptoms by blocking RGMa, an axon growth inhibitor. The model showed pathological features similar to NMO. Systemic administration of humanized monoclonal anti-RGMa antibody delayed the onset and attenuated the severity of clinical symptoms. Further, it preserved astrocytes and reduced inflammatory-cell infiltration, suggesting that targeting RGMa is effective in treating an animal model of NMO.

2O3-3 Mafb prevents excess inflammation after ischemic stroke by the clearance of DAMPs through MSR1 Takashi Shichita^1,2，Akihiko Yoshimura² ¹Stroke Renaissance, Tokyo Metro Inst Med Sci，²Dept Microbiol Immunol, School Med, Keio Univ Inflammation is an essential step for the pathology of ischemic stroke. Since no pathogen exists within brain, post-ischemic inflammation will be triggered by some endogenous molecules (DAMPs: danger associated molecular patterns), which were released from dying brain cells. We clarified the molecular mechanisms for the clearance of DAMPs from ischemic brain. Using random mutagenesis method, MSR1 (scavenger receptor) and Mafb (transcription factor) were identified as key factors for DAMP clearance. MSR1 expression levels in infiltrating mononuclear phagocytes increased from day 1 to day 3 after stroke onset, which was dependent on Mafb. These MSR1-high cells removed DAMPs efficiently and produced IGF-1, a neurotrophic factor, and therefore revealed pro-resolving phenotype. The deficiency of Msr1 or Mafb in infiltrating immune cells resulted in the exacerbation of inflammation and neuronal damages. Thus, Mafb-MSR1 pathway is important for the resolution of cerebral post-ischemic inflammation. We also found that Am80, a retinoic acid receptor agonist, enhanced MSR1 expression in infiltrating immune cells through Mafb and revealed neuroprotective effects against ischemic brain injury. Our results indicate that DAMPs regulate not only the induction but also the resolution of post-ischemic inflammation. The novel neuroprotective strategy for ischemic stroke can be developed by accelerating the endogenous pro-resolving mechanisms to prevent the excess inflammatory responses.		2O3-4 Epidermal growth factor regulates accumulation of sulfated chondroitin in the developing GABA neurons. Yuriko Iwakura¹，Yutaro Kobayashi¹，Hisaaki Namba¹，Yuichiro Watanabe²，Toshiyuki Someya²，Hiroyuki Nawa¹，Takayuki Yukawa^1,2 ¹Dept Mol Neurobiol, Brain Res Inst, Niigata Univ，²Dept Psychi, Grad Sch Med and Dent Sci, Niigata Univ Epidermal growth factor (EGF) is widely expressed in the brain. We previously reported EGF attenuates the maturation of cortical GABA neurons. Perineuronal nets (PNNs) are formed around GABA neurons along with neuronal development and implicated in their synaptic maturation and stabilization. Here we examined the effect of EGF on the production of sulfated chondroitin (CS), chondroitin sulfate proteoglycans (CSPG), and the construction of PNNs in culture and in vivo. The amounts of 4-sulfated chondroitin (C4S) and 6-sulfated chondroitin (C6S) were decreased in the EGF-treated culture. The level of CS was also influenced in cortex and hippocampus of EGF-overexpressing transgenic (EGF-Tg) mice, which is suggested to exhibit schizophrenia-like behavioral abnormalities. In agreement, our immunoblots revealed the amount of C4S was altered in the postmortem hippocampus of schizophrenia. PNNs were decreased in the EGF-treated culture and in the cortex of EGF-Tg mice. In addition, EGF influenced the aggregation of carboxyl or amino fluorescent particles around the cultured neurons. It suggests that EGF affects the accumulation of CSPG by altering electrical charges at the cell surface. These findings suggest that EGF has a regulatory role in PNNs construction by altering the production and accumulation of CS and that may contribute to the neuropathological traits of schizophrenia. This study was conducted in accordance with the ethical code stated in the Declaration of Helsinki, and was approved by the Ethics Committee of Niigata Univ. Sch. of Med. Written informed consents were obtained from the families of the control and schizophrenia patients to allow the pathologic investigation of postmortem brain. We abided by privacy confidentiality and made consideration for anonymity.

2O3-5 Visualizing changes in brain-derived neurotrophic factor (BDNF) expression using bioluminescence imaging in living mice Mamoru Fukuchi^1,4，Hironori Izumi²，Hisashi Mori²，Masahiro Kiyama³，Satoshi Otsuka³，Shoji Maki³，Yosuke Maehata⁴，Akiko Tabuchi⁴，Masaaki Tsuda⁴ ¹Lab Mol Neurosci, Fac Pharm, Takasaki Univ Health & Welfare，²Dept Mol Neurosci, Grad Sch Med & Pharm Sci, Univ Toyama，³Dept Eng Sci, Grad Sch Inform & Eng, Univ Electro-Communications，⁴Dept Biol Chem, Grad Sch Med & Pharm Sci, Univ Toyama Brain-derived neurotrophic factor (BDNF) plays a crucial role in expressing a variety of neural functions including memory consolidation. In addition, alterations of BDNF levels in the brain are associated with neurodegenerative and neuropsychiatric disorders. Therefore, it is important to understand how levels of BDNF are controlled. Recently we generated a novel transgenic mouse strain, termed the Bdnf-Luciferase transgenic (Bdnf-Luc Tg) mouse, to monitor changes in Bdnf expression. Here we detected the bioluminescence signal from living Bdnf-Luc Tg mice after intraperitoneal administration of D-luciferin. Despite high levels of Bdnf expression in the brain, it was difficult to detect a signal from the brain region, probably because of its poorly penetrable (short-wavelength) bioluminescence. However, we could detect the changes in the bioluminescence signal in the brain region using a luciferin analogue "TokeOni" generating a near-infrared wavelength of bioluminescence. We also found a strong correlation between increases in body weight and bioluminescence signal in the abdominal region of Tg mice fed a high-fat diet. These results show that changes in Bdnf expression can be visualized using living mice, and that the Tg mouse could be a powerful tool for clarification of the role of Bdnf expression in pathophysiological and physiological conditions.