一般ポスター

一般ポスター病態モデル

7月8日（土）　12:50-13:50　ポスター会場① 3P⑧-1 アデノ随伴ウイルス発現系を用いたTDP-43蓄積モデルの開発 TDP-43 accumulation model using adeno-associated virus expression system 高瀬　未菜^1,3, 勇　亜衣子¹, 毛内　拡^2,3, 野中　隆¹, 長谷川　成人¹ 1. 東京都医学総合研究所脳・神経科学研究分野, 2. お茶の水女子大学理学部生物学科, 3. お茶の水女子大学大学院人間文化創成科学研究科 Mina Takase^1,3, Aiko Isami¹, Hiromu Monai^2,3, Takashi Nonaka¹, Masato Hasegawa¹ 1. Dept. of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan, 2. Department of Biological Sciences, Ochanomizu University, Tokyo, Japan, 3. Graduate school of Humanities and Sciences, Ochanomizu University, Tokyo, Japan Amyotrophic lateral sclerosis (ALS) and some forms of frontotemporal lober degeneration (FTLD) are neurodegenerative diseases with pathological TDP-43 aggregates in neurons and oligodendrocytes, collectively referred to as TDP-43 proteinopathies. TDP-43 is a heterogenous ribonuclear protein. It is normally localized in the nucleus, but in the brains of patients, it accumulates in the cytoplasms and processes in a filamentous, phosphorylated, and ubiquitinated state. Although a number of transgenic mice overexpressing mutant TDP-43 have been generated to elucidate the mechanism of TDP-43 accumulation, they do not fully reproduce the accumulation of TDP-43 in the brains of patients. In this study, we aim to develop a novel in vivo model that reproduces abnormal accumulation of TDP-43 by using an adeno-associated virus (AAV) expression system. The AAV expressing the mutants of TDP-43 was injected into the brain of mice, and some months later, the brains were isolated for immunohistochemical and biochemical analyses. The results showed phosphorylated TDP-43-positive intracellular inclusions and insolubilization of phosphorylated TDP-43 in the brain. We're planing to further analyze the ultrastructure and other biochemical features of TDP-43 aggregates in these mice.		7月8日（土）　12:50-13:50　ポスター会場① 3P⑧-2 結節性硬化症モデルマウスでは、アストロサイトにおけるNF-κBの活性化により学習障害が生じる Activation of NF-κB signaling in astrocyte promotes memory disorder in tubular sclerosis complex model mouse 島田　忠之¹, 杉浦　弘子¹, 山形　要人^1,2 1. 東京都医学総合研究所, 2. 高田西城病院 Tadayuki Shimada¹, Sugiura Hiroko¹, Kanato Yamagata^1,2 1. Tokyo Metropolitan Institute of Medical Science Tuberous sclerosis complex (TSC) patients harbor hamartomas in the brain and other organs. The neuropsychiatric symptoms of TSC patients include refractory epilepsy, autism spectral disorders and intellectual disability. One of the responsible genes for TSC is Tsc1. To investigate if the brain astrocytes contribute to the neuropsychiatric symptoms of TSC patients, we developed astrocyte-specific Tsc1 knockout mice (cKO mouse) as a TSC model mouse and examined their phenotypes. The cKO mice exhibited increase of GFAP-highly-positive cells in the brain, especially in the hippocampus, the malformed dendritic spine formation in dentate gyrus of hippocampi, and impaired social memory by three-chamber test. We found that these phenotypes are regulated by Rheb/syntenin signaling. The loss of Tsc1 function activates the Rheb/syntenin signaling in the astrocytes and induces astrogliosis, affecting the spine morphology and neural functions by the crosstalk between the astrocytes and neurons. Further, we found that phosphorylation of NF-κB is regulated by the Rheb/syntenin in cKO mice astrocyte, and inhibition of NF-κB rescued impaired social memory. NF-κB-regulated gene expression in the astrocytes could affect neuronal morphology and function in TSC mouse. We are now trying to isolate the target gene of NF-κB that regulates social learning deficit in TSC model mice.

7月8日（土）　12:50-13:50　ポスター会場① 3P⑧-3 疾患特異的iPS細胞を用いたペリツェウス・メルツバッハ病病態モデル構築と表現系解析 Modeling and Phenotypic analysis of Pelizaeus-Merzbacher disease using patient-derived iPS cells 鈴木　禎史, リ　コウ, 後藤　雄一, 井上　健国立精神・神経医療研究センター　疾病研究第二部 Sadafumi Suzuki, Heng Li, Yu-ichi Goto, Ken Inoue Department of Mental Retardation and Birth Defect Research National Institute of Neuroscience, National Center of Neurology & Psychiatry Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive leukodystrophy characterized by diffuse hypomyelination in the central nervous system (CNS). PMD is caused by mutations in the proteolipid protein gene PLP1, which encodes the major myelin protein of the CNS. Although, genomic duplications are the most frequent causative mutation, the cellular consequences of how an extra-copy of wild-type PLP1 causes severe hypomyelination remains poorly understood. To address cellular pathology of PMD more precisely, we have been generating human induced pluripotent stem cells (hiPSCs) from patients with PMD harboring PLP1 duplication and aim to differentiate them into OLs to recapitulate the cellular pathology of PMD in culture.We observed increase of reactive oxygen species (ROS) accumulation in OPCs (OL precursor cells) in a PMD-derived hiPSC lines comparison with a normal control. We found abnormalities of process number and length of the OPCs. Similarly we detected ROS accumulation and abnormalities of morphology in OPCs in brain organoid from PMD-iPSCs. These findings suggest that the cellular phenotypes of PMD-derived hiPSCs may occur at OPC stage of OL differentiation, potentially involving ROS-induced pathology. We hypothesize that increased expression of PLP1 potentially triggers abnormal increase of ROS accumulation in OPCs, which may eventually induce hypomyelination.		7月8日（土）　12:50-13:50　ポスター会場① 3P⑧-4 マウスストレスモデルにおける膜結合型プロスタグランジンE₂合成酵素-1の役割 Role of Microsomal prostaglandin E synthase-1 in mouse models of stress 松尾　由理¹, 高木　日菜¹, 川端　悠太¹, 堂前　あすみ¹, 審良　静男², 植松　智³, 高橋　達雄¹ 1. 北陸大学　薬学部　薬学臨床系　薬理学分野, 2. 大阪大学免疫学フロンティア研究センター自然免疫学, 3. 大阪市立大学大学院医学研究科医学部ゲノム免疫学 Yuri Ikeda-Matsuo¹, Hina Takagi¹, Yuta Kawabata¹, Asumi Doumae¹, Shizuo Akira², Satoshi Uematsu³, Tatsuo Takahashi¹ 1. Lab. Pharmacol., Dept. Clin. Pharmacy, Fac. Pharmac. Sci., Hokuriku Univ., 2. Lab. Host Defense, WPI Immunol. Front. Res. Ctr, Osaka Univ., 3. Dept. Immunol. Genomics, Osaka City Univ. Grad. Sch. Med. Although there are many antidepressants, about one third of patients experience treatment-resistant depression. In this study, we investigated the involvement of microsomal prostaglandin E synthase-1 (mPGES-1), a terminal inducible enzyme for PGE₂ synthesis, in acute restraint stress (RS: 6 h) and social defeat stress (SDS). mPGES-1 mRNA was significantly increased after RS. Induction of mPGES-1 protein was observed in neurons in the frontal cortex (FC). PGE₂ in FC was also significantly upregulated in wild-type (WT) mice, but not in mPGES-1 knockout (ES1KO) mice. The inflammatory responses, such as increases in GFAP and TNF-α, observed after RS in ES1KO were significantly less than those in WT. In sucrose preference test (SPT), the ratio of sucrose intake after RS in WT was significantly less than that in ES1KO. In SDS model, upregulation of mPGES-1 was also observed in FC, amygdala and ventral tegmental area at Day1 and 4. PGE₂ in FC was significantly upregulated at Day4 in WT mice, but not in ES1KO mice. The ratio of sucrose intake at Day8 of SDS in WT was significantly less than that in ES1KO. Taken together, these results suggest that mPGES-1 is induced by both RS and SDS stress in FC, and then contributes to brain inflammation and anhedonia through PGE₂ production. Thus, mPGSE-1 may be a promising novel therapeutic target for treatment of depression.

7月8日（土）　12:50-13:50　ポスター会場① 3P⑧-5 側頭葉てんかんモデルマウス共存症（高血糖～肥満）に関わるインスリンシグナル機構について Investigation of insulin signaling in the development of obesity and diabetes caused by epileptic seizures 上窪　悠真, 田中　朋也, 利川　泰博, 太田　真菜美, 藤田　明子, 加藤　啓子京都産業大学大学院　生命科学研究科 Yuma Kamikubo, Tomoya Tanaka, Yasuhiro Togawa, Manami Ota, Akiko Fujita, Keiko Kato Division of life sciences, Kyoto Sangyo University Epilepsy is highly associated with the risk of comorbidities such as obesity, diabetes, and cardiovascular disorders. We investigated the role of insulin signaling in the obesity of a mouse model of epilepsy. In this study, we used an amygdala-kindled model, in which conscious unrestrained mice received a biphasic square wave pulse once a day. Amygdala-kindled mice showed weight gain by repeated amygdala stimulation with the increase of white adipose tissue, brown adipose tissue, and brain weight after three weeks of onset. Blood glucose levels and insulin levels were elevated. In the insulin tolerance test, amygdala-kindled mice received a load of insulin (1.5 U/kg) after amygdala stimulation, and the expression levels of the phosphorylated form of Akt and hormone-sensitive lipase (HSL) in white adipose tissue were studied via western blotting. The phosphorylation of Akt, a protein kinase that plays a central role in insulin signaling, showed no significant difference. In contrast, phosphorylation of HSL, a lipolytic enzyme whose activity is inhibited by insulin, was significantly reduced in the epilepsy model (S563: p = 0.0012, mean 37% reduction; S660 p = 0.0012, mean 73% reduction). It suggests that the elevated insulin secretion by amygdala stimulation downregulated HSL activity daily and led to obesity in amygdala-kindled mice.