一般口演
神経系疾患と治療 |
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| 7月6日（木） 16:30-18:00 Room E
1O⑧-1
Galectin-1はアルツハイマー病モデルマウスにおいて脳での軸索再伸長と記憶改善に寄与する
Galectin-1 contributes to axonal regeneration in the brain and memory recovery in Alzheimer's disease model mice
楊 熙蒙, 東田 千尋
富山大学 和漢医薬学総合研究所 神経機能学領域
Ximeng Yang, Chihiro Tohda
Section of Neuromedical Science, Inst. of Natural Medicine, Univ. of Toyama, Japan
Alzheimer's disease (AD) is a neurodegenerative disorder developed by deposition of Aβ in the brain. We previously found that diosgenin, a constituent of Dioscorea Rhizoma, recovered memory deficits in a mouse model of AD (5XFAD), and promoted long-distance axonal regeneration in 5XFAD mice brains. In the present study, we aimed to clarify molecular mechanisms for controlling accurate pathfinding of injured axons in AD brains. Axon-regenerated neurons (after diosgenin administration) in the neural circuits contributing memory formation; from the hippocampus to the prefrontal cortex (PFC), were selectively visualized by retrograde tracings. Naïve neurons and axon-regenerated neurons in the brain slices were separately captured by laser microdissection to serve DNA microarray. Galectin-1 (Gal-1) was a drastically upregulated molecule in axon-regenerated neurons. Overexpression of Gal-1 in the hippocampal neurons promoted axonal regeneration toward to the PFC and recovered memory deficits in 5XFAD mice. Gal-1 was located on the membrane of growth cones and interacted with Secernin-1 that were secreted from the PFC neurons to promote axonal guidance in this neural circuit. Our study identified Gal-1 as a key molecule for direction-specific axonal regeneration in AD brains. Elevated level of Gal-1-Secernin-1 interaction should be a novel therapeutic strategy for AD treatment. | | 7月6日（木） 16:30-18:00 Room E
1O⑧-2
脳傷害後の小胞体ストレス応答は細胞タイプに特徴的な時間依存性パターンを示す
Brain injury triggers cell-type-specific and time-dependent endoplasmic reticulum stress responses
宝田 美佳, Qiyan Fan, 沖谷 なほ子, 堀 修
金沢大学 医 神経解剖
Mika Takarada-Iemata, Qiyan Fan, Nahoko Okitani, Osamu Hori
Dept. of Neuroanat., Grad. Sch. of Med. Sci., Kanazawa University, Kanazawa, Japan
Unfolded protein response (UPR) is a signal transduction network that responds to endoplasmic reticulum (ER) stress by coordinating protein homeostasis to maintain cell viability. Despite accumulating evidence suggesting that the UPR plays a role in neurodegenerative diseases and brain insults, our understanding of how ER stress is induced under neuropathological conditions is limited. Here, we investigated the cell- and time-specific patterns of the ER stress response after brain injury using ER stress-activated indicator (ERAI) mice. ERAI mice enable monitoring of ER stress by detecting activation of X-box binding protein 1, a transducer of UPR, as fluorescence of fusion protein with Venus, a GFP variant. Following cortical stab injury of ERAI mice, the GFP signal and number of GFP+ cells increased in the ipsilateral cortex throughout the observation period. GFP signals were observed in injured neurons early after brain injury. However, non-neuronal cells, mainly endothelial cells followed by astrocytes, accounted for the majority of GFP+ cells after brain injury. Similar results were obtained in a mouse model of focal cerebral ischemia. These findings suggest that activation of the UPR in both neuronal and non-neuronal cells, especially endothelial cells and astrocytes, may play an important role in and could be a potential therapeutic target for acute brain injuries. | | 7月6日（木） 16:30-18:00 Room E
1O⑧-3
くも膜下出血のEBIによる神経炎症、細胞死のメカニズム解析研究
Mechanistic analysis study of neuroinflammation and cell death caused by EBI in subarachnoid hemorrhage
金 度潤1, 加瀬 義高1,2, 岡野 栄之1,2
1. 慶應義塾大学医学部生理学教室, 2. 藤田医科大学
Doyoon Kim1, Kase Yoshitaka1,2, Okano Hideyuki1,2
1. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, 2. Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
Subarachnoid hemorrhage (SAH) is a fatal disease, with early brain injury (EBI) occurring within 72 h of SAH injury contributes to its poor prognosis. In this study, we induced SAH in mice by injecting hematoma into prechiasmatic cistern and created models of mild to severe SAH. In sections of the mouse cerebrum, we investigated neuroinflammation and neuronal cell death in the cortex from anterior to posterior region 24 h after SAH injury. In addition, to investigate the extent to which hemoglobin and iron in the hematoma contributed to inflammation, artificial cerebrospinal fluid（aCSF）was injected in the same volume as the hematoma used in severe SAH, and the degree of inflammation was compared between the two groups.
Neuroinflammation caused by SAH spread throughout the cerebrum from anterior to posterior layers, and neuronal cell death increased in correlation with neuroinflammation. This trend increased with increasing severity. On the other hand, there was no significant difference in the degree of inflammation between the aCSF-injected and hematoma-injected models of severe SAH.
Our results suggest that reducing neuroinflammation in all layers of the cerebral cortex may improve the prognosis of SAH patients. Besides, increased intracranial pressure, rather than hemoglobin or iron in the hematoma, may contribute to neuroinflammation in SAH to a greater extent. | | 7月6日（木） 16:30-18:00 Room E
1O⑧-4
海馬硬化症における異常神経回路を同定するマーカープローブの確立
Human GAP-43 phospho-T181 is a marker of abnormal neuronal circuits in hippocampal sclerosis
岡田 正康1, 北浦 弘樹2,3, 玉田 篤史4, 六車 恵子4, 柿田 明美3, 福多 真史5, 棗田 学1, 大石 誠1, 藤井 幸彦1, 五十嵐 道弘6
1. 新潟大学 脳研究所 脳神経外科学分野, 2. 公立小松大学 保健医療学部 臨床工学科, 3. 新潟大学 脳研究所 病理学分野, 4. 関西医科大学 医学部 iPS・幹細胞応用医学講座, 5. 西新潟中央病院 機能脳神経外科, 6. 新潟大学大学院 医歯学総合研究科 神経生化学分野
Masayasu Okada1, Hiroki Kitaura2,3, Atsushi Tamada4, Keiko Murguma4, Akiyoshi Kakita3, Masafumi Fukuda5, Manabu Natsumeda1, Makoto Oishi1, Yukihiko Fujii1, Michihiro Igarashi6
1. Dept Neurosurg, BRI, Niigata Univ, Niigata, Japan, 2. Dept of Clin Engineering, Fac Health Sci, Komatsu Univ, Ishikawa, Japan, 3. Dept Pathol, BRI, Niigata Univ, Niigata, Japan, 4. Dept iPS Cell Applied Med, Kansai Med Univ, Osaka, Japan,, 5. Div of Func Neurosurg, NHO Nishiniigata Chuo Hosp, Niigata, Japan, 6. Dept of Neurochem and Mol Cell Biol, Sch Med & Grad Sch Med Dent Sci, Niigata Univ, Niigata, Japan
Growth-associated protein-43 kDa (GAP-43) is related to neuronal circuit formation. We recently identified mouse GAP-43 phospho-threonine 172 (pT172) antibody as a marker of growing axons by phosphoproteome analysis prepared from the growth cones of developing rodent brain (Okada et al. 2021). Mesial temporal lobe epilepsy (MTLE) caused by hippocampal sclerosis has been reported to result in neuron degeneration in the dentate hilus and abnormal nerve sprouts in the granule cell layer (GCL) of the dentate gyrus (DG), which is probably involved in abnormal neuronal circuit formation. However, there have been no previous reports on GAP-43 phosphorylation.
Primate pT181 corresponds to rodent pT172, and we applied this antibody (pT181) to human brain processes and pathologies, including MTLE. We obtained the following results: (1) JNK is a kinase responsible for human pT181; (2) using human iPS cell-derived cerebral organoids, we biochemically identified pT181; (3) we acquired the Flavoprotein Fluorescence Ex Vivo Imaging at the GCL of the DG in human hippocampal tissue of MTLE patients (All patients provided written informed consent). The signal changes correlated with the pT181-immunostaining intensity of the GCL. Taken together, the pT181 antibody is a marker probe to detect growing axons during human development and the abnormal neuronal circuit causing intractable epilepsy. | | 7月6日（木） 16:30-18:00 Room E
1O⑧-5
iPS細胞由来ミクログリアの誘導法と疾患モデリング
Generating Microglia from human iPS Cells and Disease Modeling
孫 怡姫, 渡部 博貴, 森本 悟, 岡野 栄之
慶應義塾大学医学部 生理学教室
Iki Sonnn, Hirotaka Watanabe, Satoru Morimoto, Hideyuki Okano
Department of Physiology, Keio University School of Medicine
近年、ミクログリアの異常な活性化に関与する中枢神経疾患が多数報告された。そのため、脳内免疫細胞の活性化あるいは機能破綻メカニズムは、中枢神経疾患治療における重要なターゲットである。本研究では、ヒトiPS細胞からミクログリアの分化誘導法を開発し、ミクログリアに起因する疾患のモデリングを探索した。まず、先行研究に基づき独自に改変したプロトコルを作成した。Tet onシステムを利用し、ミクログリアの発生に重要な転写因子であるPu.1を一時的に過剰発現させることで、約2週間で大量なミクログリア(hiMGL)を分化誘導することに成功した。FACSやRNA-Seqなどの手法を用い、hiMGLの性質について評価を行い、hiMGLはヒトミクログリアと類似した機能を持つことを確認できた。次に、病態解析の手法を考案した。Primary microgliopathyと考えられている那須-ハコラ病(Nasu-Hakola Disease, NHD) をモデルとして解析を試みた。まずは、NHD患者からhiMGLの分化誘導を行った。NHDの臨床特徴である白質脳症に着目し、NHD-hiMGLのミエリンに対する、およびその炎症反応について詳細な解析を行い、DAP12の変異により、ミクログリアの炎症反応に障害を引き起こすと結論した。本研究では、ミクログリア障害を端緒とした神経疾患での脳内免疫破綻の網羅的な理解、および治療法開発を目指してる。 | | 7月6日（木） 16:30-18:00 Room E
1O⑧-6
LRP12のCGGリピート伸長は筋萎縮性側索硬化症の原因となる
CGG repeat expansion in LRP12 causes amyotrophic lateral sclerosis
久米 広大1, 倉重 毅志2, 六車 恵子3, 森野 豊之4, 多田 有似1, 菊本 舞1,5, 中森 正博5, 小笠原 真志6, 江浦 信之6, 中山 宜昭7, 伊東 秀文7, 中村 正孝8, 陸 雄一9, 岩崎 靖9, 丸山 博文5, 青木 洋子10, 和泉 唯信11, 青木 正志12, 川上 秀史1
1. 原爆放射線医科学研究所 分子疫学, 2. 呉医療センター 脳神経内科, 3. 関西医科大学 iPS・幹細胞応用医学, 4. 徳島大学 遺伝情報医学, 5. 広島大学 脳神経内科, 6. 国立精神神経医療研究センター 疾病研究第一部, 7. 和歌山医科大学 脳神経内科, 8. 関西医科大学 神経内科, 9. 加齢医科学研究所 神経病理, 10. 東北大学 遺伝医療学, 11. 徳島大学 脳神経内科, 12. 東北大学 神経内科
Kodai Kume1, Takashi Kurashige2, Keiko Muguruma3, Hiroyuki Morino4, Yui Tada1, Mai Kikumoto1,5, Masahiro Nakamori5, Masashi Ogasawara6, Nobuyuki Eura6, Yoshiaki Nakayama7, Hidefumi Ito7, Masataka Nakamura8, Yuichi Riku9, Yasushi Iwasaki9, Hirofumi Maruyama5, Yoko Aoki10, Yuishin Izumi11, Masashi Aoki12, Hideshi Kawakami1
1. Dept. of Molecular Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima, Japan, 2. Dept. of Neurology, Kure Medical Center, Hiroshima, Japan, 3. Dept. of iPS Cell Applied Medicine, Kansai Medical Univ., Osaka, Japan, 4. Dept. of Medical Genetics, Tokushima Univ., Tokushima, Japan, 5. Dept. of Clinical Neuroscience and Therapeutics, Hiroshima Univ., Hiroshima, Japan, 6. Dept. of Neuromuscular Research, National Centre of Neurology and Psychiatry, Tokyo, Japan, 7. Dept. of Neurology, Wakayama Medical Univ., Wakayama, Japan, 8. Dept. of Neurology, Kansai Medical Univ., Osaka, Japan, 9. Dept. of Neuropathology, Institute for Medical Science of Aging, Nagakute, Japan, 10. Dept. of Medical Genetics, Tohoku Univ., Miyagi, Japan, 11. Dept. of Neurology, Tokushima Univ., Tokushima, Japan, 12. Dept. of Neurology, Tohoku Univ., Miyagi, Japan
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn’t fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12, who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in ALS, a finding reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in ALS than in OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes. | |
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