一般口演
グリア機能と疾患 |
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| 7月6日（木） 16:30-17:45 Room C
1O⑥-1
急性神経炎症は、ドーパミン受容体D1Rを介してミクログリアの炎症を抑制するドーパミンサージを引き起こす
Acute neuroinflammation triggers a dopamine surge that suppresses microglial inflammation via its dopamine receptor D1R
チョードリ モハメッド エ1,2,3, 西川 裕喜2, 山本 温人3, 矢野 元1, 永井 将弘3, 萬家 俊博2, 田中 潤也1
1. 愛媛大学医学系研究科分子細胞生理学, 愛媛県東温市志津川454, 2. 愛媛大学大学院医学系研究科麻酔周術期科学, 愛媛県東温市志津川454, 3. 愛媛大学大学院医学系研究科臨床薬理学, 愛媛県東温市志津川454
Mohammed E Choudhury1,2,3, Yuki Nishikawa2, Haruto Yamamoto3, Hajime Yano1, Masahiro Nagai3, Toshihiro Yorozuya2, Junya Tanaka1
1. Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 2. Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 3. Department of Clinical Pharmacology and therapeutics, Ehime University Graduate School of Medicine, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime
Systemic infection is an important factor in developing delirium, which is characterized by irregular neural activity and may be associated with a strained microglial reaction in delirium. In this study, a delirium model was established by administering LPS to adult male rats which displayed sleep-wake disturbances as well as increased dopamine (DA) levels in the PFC following 21 h after LPS administration. Increased cytokines expression was observed in sorted microglia from the PFC of the delirium model; however, tumor necrosis α (TNFα), was sharply decreased 21 h after LPS administration. We also found that primary cultured and sorted rat microglia notably express the dopamine D1 receptor (D1R) and D4R, but not D2R, D3R, or D5R. In response to a D1R-specific agonist SKF-81297 (SKF), the cultured microglia showed increased intracellular cAMP levels. DA and SKF suppressed lipopolysaccharide (LPS)-induced expression of IL-1β and tumor necrosis α (TNFα) in cultured microglia. A D1R antagonist SCH23390 (SCH) partially abolished the TNFα expression change. Administration of the DA precursor L-DOPA or SKF to the delirium model rats repressed the expression of IL-1β and TNFα. Overall, our data suggest that D1R in microglia mediates the suppressive effects of LPS-induced microglia mediated neuroinflammation supporting its therapeutic efficacy against delirium against delirium. | | 7月6日（木） 16:30-17:45 Room C
1O⑥-2
SARS-CoV-2は変異を介してもミクログリアへの感染性が強い
SARS-CoV-2 has high infectivity to microglia regardless of mutations.
後藤 真楽1,2, 加瀬 義高1,3, 孫 怡姫1, 村上 玲1, 佐藤 月花1, 岡野 栄之1,3
1. 慶応義塾大学 医学部生理学教室, 2. 東京大学 医学部医学科, 3. 藤田医科大学 精神・神経病態解明センター
Maraku Goto1,2, Yoshitaka Kase1,3, Iki Sonn1, Rei Murakami1, Tsukika Sato1, Hideyuki Okano1,3
1. Dept. of Physiol., Univ. of Keio, Tokyo, Japan, 2. Faculty of Medicine., Univ. of Tokyo, Tokyo, Japan, 3. International Center for Brain Science., Fujita Health University, Tokyo, Japan
Although COVID-19 has been reported to cause CNS symptoms, it has not been elucidated which types of cells in central nervous system are susceptible to infection by SARS-CoV-2 and whether there are differences in infectivity among mutations.Therefore, we generated cortical neurons, astrocytes, microglia and brain organoids from human iPS cells and investigated the infectivity of pseudo-lentiviruses expressing S proteins of SARS-CoV-2 alpha, delta and omicron strains.Infection was not observed in cortical neurons and astrocytes, while microglia were infected by each pseudo-lentivirus. Furthermore, the experiment using brain organoids revealed that each pseudo-lentivirus variant infected neither neurons nor neural stem/progenitor cells.In addition, the expression analysis revealed that the expression of DPP4, which is a candidate receptor for SARS-CoV-2 adsorption in the CNS, was significantly higher in microglia, but lower in other cells, suggesting that DPP4 is an important factor in CNS infection.Through this study, we concluded that inflammation caused by microglial infection, rather than infection in neurons, is the key factor in CNS symptoms of COVID-19. | | 7月6日（木） 16:30-17:45 Room C
1O⑥-3
前頭側頭型認知症及び筋萎縮性側索硬化症関連分子Rab39bはオリゴデンドログリア細胞も制御する
FTDALS1-associated gene product Rab39b uniquely affects oligodendroglial cell differentiation
磯貝 幹典, 白井 玲美奈, 山内 淳司
東京薬科大学 生命科学部 分子神経科学研究室
Mikinori Isogai, Remina Shirai, Junji Yamauchi
Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences
Frontotemporal dementia (FTD) is a type of degenerative dementia in which the frontal and temporal lobes atrophy. Amyotrophic lateral sclerosis (ALS) is a disease in which motor nerve cells throughout the body degenerate. The degeneration of neuron and the reduction of oligodendrocytes induces these diseases. C9orf72, which is FTD and ALS-responsible gene, acts as a molecular switch for a variety of molecules, including Rab39b.Previous research shows that the levels of Rab39b are significantly altered during the differentiation of neural progenitor cells by RNA-Seq. In this study, knockdown of Rab39b significantly suppressed cell differentiation in the FBD-102b cell line, which is the oligodendroglial cell model.These results indicate that knockdown of Rab39b, which is associated with FTD and ALS, suppresses morphological differentiation of oligodendroglial cells.We expect that these results may help to identify the causes of FTD and ALS, the responsible gene products may be promising therapeutic target candidates. | | 7月6日（木） 16:30-17:45 Room C
1O⑥-4
ミューラー細胞のCDC42EP4欠損によるグルタミン酸回収異常は視神経症を誘発する
Impaired glutamate clearance by CDC42EP4 deficiency in Muller cells causes optic neuropathy
篠崎 陽一1,2, 武田 詩穂1, 坂井 謙斗1,2, 繁冨 英治1,2, 柏木 賢治3, 行方 和彦4, 原田 高幸4, 木下 専5, 小泉 修一1,2
1. 山梨大 院 医 薬理, 2. 山梨大 GLIAセンター, 3. 山梨大院 医 眼科, 4. 東京都医学研 視覚病態, 5. 名古屋大院 理 細胞制御
Youichi Shinozaki1,2, Shiho Takeda1, Kento Sakai1,2, Eiji Shigetomi1,2, Kenji Kashiwagi3, Kazuhiko Namekata4, Takayuki Harada4, Makoto Kinoshita5, Schuichi Koizumi1,2
1. Dept. Neuropharmacol., Interscp. Grad. Sch. Med., Univ. Yamanashi, Yamanashi, Japan, 2. GLIA centr., Univ. Yamanashi, 3. Dept. Ophthalmol., Interscp. Grad. Sch. Med., Univ. Yamanashi, Yamanashi, Japan, 4. Vis. Res. Project, Tokyo Metr. Inst. Med. Sci., Tokyo, Japan, 5. Div. Biol. Sci., Dept. Mol. Biol., Nagoya Univ. Grad. Sch. Sci., Aichi, Japan
Glaucoma, progressive optic neuropathy, is leading cause of blindness worldwide. Retinal ganglion cells (RGCs), a retinal subtype of neurons transduces visual information to the brain, are the most sensitive to glaucoma, and their damages impair visual function. Although an elevated intraocular pressure (IOP) is well known, the majority of Japanese patients with glaucoma has normal IOP (i.e. normal tension glaucoma, NTG). Excitotoxicity by excess glutamate (Glu) is one of the possible cause of NTG. Here, we show CDC42EP4 as a new molecular target for development of NTG because its deficiency causes NTG-like pathology. We first investigated expression pattern of CDC42EP4 in various brain regions and retina, and revealed its highest expression in the retina. CDC42EP4KO mice showed age-associated loss of RGCs and impaired visual function without IOP elevation. We then asked which cell type expresses CDC42EP4 and revealed that Muller cells, horizontal cells, and a part of bipolar cells expressed CDC42EP4. Previous cerebellum study has shown that CDC42EP4 in Bergmann glia controls localization of glutamate (Glu) transpoter. We found that the KO mice showed elevated Glu level in the aqueous humor. Associated with this, the KO mice also showed reduction in Slc1a3 gene expression, GLAST/EAAT protein expression in the retina and its surface expression in Muller cells. | | 7月6日（木） 16:30-17:45 Room C
1O⑥-5
膠芽腫における細胞周期依存的な核膜ストレス応答の変動
The response to Nuclear Envelope Stress is associated with cell cycle in Glioblastoma
上川 泰直, 呉 祖倩, 齋藤 敦, 今泉 和則
広島大学大学院医系科学研究科分子細胞情報学
Yasunao Kamikawa, Zuqian Wu, Atsushi Saito, Kazunori Imaizumi
Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University
The nuclear envelope (NE) is frequently damaged by mechanical stresses including radial migration of neural progenitors and invasion of tumor cells. These types of stresses are called as NE stress. It has been proposed that NE stress is related to a variety of diseases such as neurodegenerative diseases and cancer through the rupture of the NE. In response to NE rupture, several factors involved in reassembly of the NE after mitosis accumulate to the damaged sites, and reseal the NE. Although many NE repair factors drastically change their localization during cell cycle, the links between NE repair and cell cycle remains unclear. In this study, we compared NE stress response among different cell lines derived from distinct types of cancers. A cell line derived from glioblastoma (GBM) U251MG exhibited nuclear deformation together with massive DNA damage. In contrast, U87MG, another cell lines derived from GBM only revealed mild nuclear deformation without DNA damage. Time-lapse imaging showed that NE repair is occasionally failed in U251MG but not in U87MG. These results indicate that the failure of NE repair causes sensitivity to NE stress in U251MG. Our data further suggest that fraction of G1-phase cells is higher in U87MG than in U251MG and G1-phase cells are more resistant to NE stress than S- and G2-phases cells. | | | |
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