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公募シンポジウム15【老化・病態における神経血管ユニットの破綻】 2021/10/1　16:00～18:00　ZOOM C会場 S15-1 ダウン症の脳発生における神経血管ユニットの破綻の可能性 Department of Pathological Biochemistry, Kyoto Pharmaceutical University ○石原 慶一 京都薬科大学 病態生化学 ○Keiichi Ishihara Department of Pathological Biochemistry, Kyoto Pharmaceutical University Down syndrome (DS) caused by triplication of human chromosome 21 is one of the most frequent aneuploidies. The analysis of postmortem brain obtained from fetus with DS indicates delayed brain development with decreasing neurogenesis in the prenatal brain with DS. To understand the mechanism of delayed brain development in DS, we analyzed DS mouse models bearing an extra copy of mouse chromosome 16, which is orthologous to human chromosome 21. We have demonstrated that the prenatal cortical neurogenesis is reduced in the embryonic cerebral cortex of DS model mice similarly to people with DS. DNA microarray analysis of embryonic brain from a DS model mouse revealed that elevated expression of inflammatory-related genes and reduced expression of development-associated genes. We have verified triplication of the trisomic Erg gene, which is predominantly expressed in endothelial cells increased the expression of inflammatory-related genes. In addition, we also demonstrated that triplicated Erg gene increased number of monocytes and neutrophils, suggesting that increased permeability of the blood vessels in the brain of DS fetus.　We also identified the decreased expression of a development-related gene, Tbx1. Since this gene is suggested to associate with brain vascularization in mice, we are focusing on the development of brain vessel in the DS model mice. We have assumed abnormality of neurovascular coupling possibly contributes the developmental delay in DS. 2021/10/1　16:00～18:00　ZOOM C会場 S15-2 血液脳関門バリア機能変動要因としてのミクログリア Microglia can be a blood-brain barrier functional regulator ○最上(重本) 由香里,佐藤 薫 国立医薬品食品衛生研究所 薬理部第一室 ○Yukari Shigemoto-Mogami, Kaoru Sato Division of Pharmacology, National Institute of Health Sciences Microglia, the brain immuno cells, maintain homeostasis of the central nervous system (CNS) through various physiological functions. In many CNS disorders with neuroinflammation, the blood-brain barrier (BBB) is reported to be disrupted, but little is known about the disruption mechanism and the involvement of microglia. We previously suggested that inflammatory activated microglia trigger the collapse of BBB. Our data also suggested that the interaction between microglia and neurovascular unit (NVU) constituent cells determines the concentrations of cytokines and chemokines thereby inducing BBB disruption. On the other hand, we have got some key data showing that the interaction between microglia and NVU cells is also important for the BBB formation in brain development. Microglia seem to contribute to the BBB functional maturation by regulating the concentration of cytokines and chemokines around blood vessels in this case also. Clarifying the difference in the interactions between microglia and NVU cells in the above two cases will lead to new therapeutic strategies and drug discovery for the CNS diseases. 2021/10/1　16:00～18:00　ZOOM C会場 S15-3 アストロサイト発生の基礎、およびその神経発達障害との関連 Basic principles of astrocyte development and their relations to neurodevelopmental disorders ○田畑 秀典 愛知県医療療育総合センター発達障害研究所 分子病態研究部 ○Hidenori Tabata Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center Astrocytes are the most abundant cell type in mammalian brains. They play essential roles not only in physiological functions, but also in the neural network formation through regulating synaptogenesis and synapse elimination during the cortical development and maturation, suggesting that their functional deficits may cause neurodevelopmental disorders. Despite their potential importance, how astrocytes are generated and positioned during development are poorly understood. In this presentation, we will show the characteristic movements of astrocyte progenitors migrating from the ventricular zone to the cortical plate (CP). In the developing mouse cerebral cortex, astrocyte progenitors move rapidly and almost randomly within the intermediate zone and the CP. We call this mode of migration “erratic migration”. On the other hand, we also observed astrocyte progenitors frequently migrate along the blood vessels, especially in the superficial CP. We will discuss the molecular mechanisms of the blood vessel-guided migration, and its importance for final positioning of astrocytes. The migration and positioning of astrocytes during the perinatal period can be affected by genetic and environmental factors. As one of the environmental factors, we are focusing on hypoxic ischemic encephalopathy. In its mouse model, the blood vessel-guided migration and final positioning of astrocytes were affected. We will also discuss the neuronal phenotypes of these mice and causality with the observed astrocytic defects. 2021/10/1　16:00～18:00　ZOOM C会場 S15-4 脳血管新生および老化における細胞周囲環境としてのプロテオグリカンの役割 Proteoglycan contributes to pericellular environment to enhance brain angiogenesis ○水谷 健一 神戸学院大学大学院 薬学研究科 ○Ken-ichi Mizutani Graduate School of Pharmaceutical Sciences, Kobe Gakuin University The brain’s vascular system is highly organized to efficiently deliver oxygen and glucose to its tissues. Recently our study showed that capillary vessels form stereographically brain-specific 3D patterning, although the characteristics of the endothelial cells that acquire brain-specific properties are still poorly clarified. During embryonic development, when unfavorable distribution of vascular networks interferes with the normal development of tissues. In contrast, brain vasculature undergoes many structural and functional alterations during aging. In this study, we focused on the aggrecan-type proteoglycan as a pericellular environment in brain endothelial cells, during vascular development and aging. We utilized VEGFR (vascular endothelial growth factor receptor) 1-DsRed::VEGFR2-GFP BAC transgenic mice that expressed both red and green fluorescent protein in vascular endothelial cells to visualize brain capillaries, and we found the specific localization of abundant aggrecan-type proteoglycan in both VEGFR1- and VEGFR2-positive capillary vessels, whereas their expression level was disappeared in the aged brain compared with those in young brain. Moreover, our results of the ex vivo ring assay and in vitro tube formation assay revealed that aggrecan-type proteoglycan significantly enhanced the angiogenic potential. These results suggest that an important role of aggrecan-type proteoglycan as a pericellular component to enhance and maintain the angiogenic potential in the brain capillary vessels.