共同企画

共同企画合同シンポジウム神経炎症・免疫・病理から俯瞰する精神・神経疾患研究

7月7日（金）　8:30-10:30　Room B 2JS①-1 認知症におけるタウと炎症のクロストーク Cross talk between tauopathy and neuroinflammation 佐原　成彦量子科学技術研究開発機構　量子医科学研究所 Naruhiko Sahara National Institutes for Quantum Science and Technology, Institute for Quantum Medical Science Tauopathy is characterized by the intracellular fibrillar tau accumulation in central nervous system. Neuroinflammation is considered to play important roles in neurodegenerative disease progression. However, it is still unclear whether neuroinflammation is a cause or a result of neurodegeneration. We demonstrated in vivo imaging such as tau-PET, TSPO-PET and volumetric MRI on a mouse model of tauopathy. Our studies confirmed that microglial TSPO accumulation was the late event during pathological process of tauopathy. As a counterpart of activated microglia, homeostatic microglia were concomitantly reduced with pathological tau accumulation. In agreement with our finding, other group reported that several tauopathy mouse models show remarkable changes of microglia phenotype. In this talk, I will review recent works on tauopathy-associated microglia and discuss future perspectives for investigating the relationship between neurodegeneration and neuroinflammation.		7月7日（金）　8:30-10:30　Room B 2JS①-2 RGMは脳神経疾患の病態下でグリアおよび免疫機能を制御する Repulsive guidance molecule regulates glial and immune function under neurological diseases 山下　俊英大阪大学　医　分子神経科学 Toshihide Yamashita Dept. Mol. Neurosci., Grad. Sch. Med., Osaka Univ., Japan Repulsive guidance molecule-a (RGMa) is expressed in glial cells and immune cells. RGMa was recognized as the protein that regulates axon growth negatively in the adult central nervous system (CNS). Enhanced recovery of skilled forelimb movement as well as neural rewiring was observed after spinal cord injury (SCI) in adult macaque monkey following anti-RGMa antibody treatment. The international clinical trials of humanized anti-RGMa antibody (Unasnemab) for SCI is ongoing currently. Furthermore, RGMa was shown to be involved in immune regulation. RGMa expressed in dendritic cells promotes activation of T cells, leading to deterioration of autoimmune encephalomyelitis. Under the condition of neuromyelitis optica (NMO), RGMa was expressed by the neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4-IgG-induced astrocytopathy, neutrophil infiltration and clinical exacerbation were ameliorated by anti-RGMa antibody treatment. Macrophages accumulated in the lesion expressed CXCL2, and RGMa directly regulated CXCL2 expression in macrophages. RGMa also regulates blood-brain barrier integrity and cell survival in the CNS. The multiple modes of actions of anti-RGMa antibody may explain the potent effects on the neurological diseases. The clinical trial of Unasnemab for HTLV-1-associated myelopathy is also ongoing.

7月7日（金）　8:30-10:30　Room B 2JS①-3 ヒト血液単球由来iMG細胞を用いたリバーストランスレーショナル研究：患者のミクログリア活性化をin vitroで予測する Reverse translational research using human blood induced microglia-like (iMG) cells 加藤　隆弘¹, 扇谷　昌宏^1,2, 稲嶺　翔吾¹, 白水　寛理³, 前原　直樹³, 久良木　聡太¹, 田中　俊也³, 秦　暢宏³ 1. 九州大学大学院　医学研究院　精神病態医学, 2. 旭川医科大学　医学部　解剖学教室, 3. 九州大学大学院　医学研究院　脳神経外科学分野 Takahiro A. Kato¹, Masahiro Ohgidani^1,2, Shogo Inamine¹, Noritoshi Shirozu³, Naoki Maehara³, Sota Kyuragi¹, Shunya Tanaka³, Nobuhiro Hata³ 1. Dept.Neuropsychiatry, Grad.Sch.Med.Sci., Kyushu Univ., Fukuoka, Japan, 2. Dept.Functional Anat&Neuroscience, Asahikawa Med. Univ., Asahikawa, Japan., 3. Dept.Neurosurgery, Grad.Sch.Med.Sci., Kyushu Univ., Fukuoka, Japan Postmortem brain analysis and PET imaging analysis are two major methods to assess microglial activation in human, and these studies have suggested activation of human microglia in the brain of patients with various neurological and psychiatric disorders. However, by using the above methods, only limited aspects of microglial activation can be measured. We have originally developed a technique to create directly induced microglia-like (iMG) cells from fresh human peripheral blood monocytes adding GM-CSF and IL-34 for 2 weeks, instead of brain biopsy and iPS technique (Ohgidani, Kato et al. Sci Rep 2014). Using the iMG cells, dynamic morphological and molecular-level analyses such as phagocytosis and cytokine releases after cellular-level stress exposures are applicable. Recently, we have confirmed the similarity between human iMG cells and brain primary microglia by RNAseq (Tanaka, et al. Front Immunology 2021). We believe that patients-derived iMG cells will take a role as one of the important surrogate markers to predict microglial activation in patients with various neurological and psychiatric disorders. In this symposium, we will introduce our latest findings using iMG cells with such patients.		7月7日（金）　8:30-10:30　Room B 2JS①-4 Histological and molecular studies of primary microgliopathies using autopsied human brains 他田　真理新潟大学脳研究所　病理学分野 Mari Tada Dept. of Pathol., Brain Research Institute, Niigata Univ., Niigata, Japan Hereditary diffuse leukoencephalopathy with spheroids (HDLS) and Nasu-Hakola disease (NHD) are progressive dementing disorders characterized by widespread white matter degeneration. Since CSF1R and DAP12/TREM2, the respective causative genes of each disease, are selectively expressed by microglia in the CNS, and affect microglial proliferation and function, these diseases have been considered primary microgliopathies. In the brains of patients with HDLS, we and other groups have reported several histological characteristics including loss of homeostatic microglia, and alterations of microglial distribution and morphology. Consistent with these findings, bulk RNA-seq analyses of the brains of patients with HDLS have revealed downregulation of microglial marker genes including P2RY12 and CX3CR1. In the brains of patients with NHD, although microglial alterations have not been identified histologically, single-nucleus RNA-seq analyses have revealed a unique microglial signature indicating upregulation of the RUNX1, STAT3, and TGF-β pathways that mediate tissue repair responses. These findings obtained from analyses of autopsied brains have been considered direct evidence for characterization of HDLS and NHD as primary microgliopathies. Further investigations are needed to clarify the mechanisms responsible for this type of leukoencephalopathy.