公募シンポジウム

公募シンポジウム神経精神疾患の克服に向けた新たな分子治療標的の探索

7月8日（土）　13:50-15:50　Room G 3SY⑤-1 Aβ暴露アストロサイトによるシナプス病態の発現とヒトiPS細胞の活用 Synaptic abnormality by Aβ-exposed astrocytes, and utilization of human-induced pluripotent stem cell-derived astrocytes 桂林　秀太郎¹, 大藪　康平², 内野　鉱也¹, 田中　泰圭³, 窪田　香織¹, 渡辺　拓也¹, 廣瀬　伸一⁴, 岩崎　克典¹ 1. 福岡大学　薬学部　臨床疾患薬理学研究室, 2. 福岡大学　薬学部　医薬品情報学研究室, 3. 福岡大学　薬学部　応用薬剤学研究室, 4. 福岡大学　医学部　総合医学研究センター Shutaro Katsurabayashi¹, Kohei Oyabu², Kouya Uchino¹, Yasuyoshi Tanaka³, Kaori Kubota¹, Takuya Watanabe¹, Shinichi Hirose⁴, Katsunori Iwasaki¹ 1. Dept. of Neuropharm., Fac. of Pharm. Sci., Fukuoka Univ., Fukuoka, Japan, 2. Dept. of Drug Info. and Trans. Res., Fac. of Pharm. Sci., Fukuoka Univ., Fukuoka, Japan, 3. Dept. of Pharm. Care and Hlth. Sci., Fac. of Pharm. Sci., Fukuoka Univ., Fukuoka, Japan, 4. Gen. Med. Res. Ctr., Sch. of Med., Fukuoka Univ., Fukuoka, Japan Alzheimer's disease (AD) is a progressive neurodegenerative disease that presents with cognitive and behavioral disorders. Aβ_25-35 is considered an initiator in the development of AD because it causes synaptic dysfunction and synaptic loss. Since astrocytes, a type of glial cells, play an important role in the regulation of neurotransmission and synapse formation in information processing in the central nervous system, there is a concern that astrocytes may be somehow affected in synaptic function and morphology when they are damaged by Aβ_25-35. In this symposium, we will present an example of synaptic pathology caused by Aβ-exposed astrocytes, where the single-wild type neuron was co-cultured with astrocytes exposed to Aβ_25-35 beforehand. Since astrocyte pathogenesis affects synaptic function, it is expected that new drug efficacy evaluation models focusing on astrocyte pathology and treatment will be developed. Therefore, as a new experimental model, we would like to present a neuronal culture preparation using astrocytes-derived human-induced pluripotent stem cells (iPSC) as well in this symposium.		7月8日（土）　13:50-15:50　Room G 3SY⑤-2 カルシウムシグナル賦活化を介した認知機能改善機序 Pathological mechanism of cognitive disorders on collapse of calcium homeostasis 森口　茂樹東北大学　大学院薬学研究科　医薬品開発研究センター Shigeki Moriguchi RCPD, Grad. Sch. Pharmazeut. Sci., Tohoku Univ., Sendai, Japan We previously reported a novel target of the drug memantine, ATP-sensitive K⁺ (KATP) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer’s disease (AD) model mice. Memantine also inhibited Kir6.1 and Kir6.2 KATP channels and elevated intracellular Ca²⁺ concentrations in neuro2A (N2A) cells overexpressing Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed at postsynaptic regions of hippocampal neurons, whereas Kir6.1 was predominant in dendrites and cell bodies of pyramidal neurons. We confirmed that Kir6.2 mutant mice exhibit severe memory deficits and impaired hippocampal LTP, impairments that cannot be rescued by memantine administration. In the present study, we focus the complex resinous substance, propolis that is relevant as a therapeutic target for AD. We confirmed that propolis further enhances the rescue of cognitive deficits by the memantine in AD model mice. In in vitro studies, propolis significantly increased intracellular Ca²⁺ concentration and calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation in Kir6.2-overexpressed N2A cells treated with memantine. Our study demonstrates that propolis increases ATP contents and promotes the amelioration of cognitive deficits rescued by memantine via Kir6.2 channel inhibition in the CA1 region.

7月8日（土）　13:50-15:50　Room G 3SY⑤-3 タンパク質代謝不全が脳機能に与える影響 Altered protein metabolism and its effect on brain function 照沼　美穂新潟大院　口腔生化学, 新潟市, 日本 Miho Terunuma Div. of Oral Biochem., Niigata Univ, Niigata, Japan High protein diets have become popular worldwide to stay healthy. However, protein intake may result in increased ammonia production. Ammonia is a potent neurotoxin that causes severe damage to the central nervous system. It is formed in nearly all tissues of the vertebrate organism, and is a byproduct of cellular metabolism. Deficient hepatic urea formation and bacterial infection in the gut are the major causes of pathological accumulation of ammonia, which results in hyperammonemia.We have recently found that ammonia increases the amount of mature amyloid precursor protein (APP) in astrocytes, the largest and most prevalent type of glial cells in the central nervous system, and induces amyloid beta (Aβ) production.The enhanced production of Aβ in astrocytes induced by ammonia was specific to Aβ42, a principal component of senile plaques in AD patients. Furthermore, we found that hyperammonemia induces down-regulation of glutamine synthetase (GS), an enzyme that metabolizes both glutamate and ammonia in the brain. Hyperammonemia also lead to astrocyte aging. Therefore, preventing the accumulation of blood ammonia as well as ammonia in the brain maybe the key to keep healthy brain.		7月8日（土）　13:50-15:50　Room G 3SY⑤-4 高齢者の精神的健康を維持するために－認知症予防における分子標的としてのオキシトシンの可能性－ Maintaining mental health in the elderly: oxytocin as a molecular target to prevent the onset of dementia 溝口　義人佐賀大学医学部　精神医学講座 Yoshito Mizoguchi Dept. of Psychiatry, Saga University Oxytocin (Oxytocin; OXT), which is deeply involved in parent-child relationship formation and parenting behaviors, plays an important role in maintaining social connectedness, such as increasing attachment and trust in others and improving social cognition, and might exert its effect in preventing social isolation and reducing the risk of developing dementia. In the Kurokawa-cho study, the relationship between serum oxytocin concentration and cognitive function and the results of head MRI imaging analysis were examined. The older adults with higher serum oxytocin concentrations performed better on logical memory tasks and retained more hippocampal volume 7 years later. The results of this study suggest that oxytocin may positively affect cognitive function in the elderly, especially in emotionally unmediated information processing and memory. Future intervention studies on the role of OXT in memory, such as those examining the effects of intranasal OXT administration in the elderly, will be important. OXT is expected to play an even greater role in psychiatric treatment of the elderly, including the prevention of dementia. In the symposium, I will present the latest findings on possible role of oxytocin as a molecular target to maintain mental health in the elderly, including the prevention of the onset of dementia.

7月8日（土）　13:50-15:50　Room G 3SY⑤-5 社会的ひきこもりの臨床と基礎の橋渡しによるバイオマーカー創出と支援法の開発 Development of biomarker-based support system for hikikomori: Translation between clinical and basic science. 加藤　隆弘¹, 松島　敏夫¹, 久良木　聡太¹, 松尾　敬太朗¹, 瀬戸山　大樹² 1. 九州大学大学院　医学研究院　精神病態医学, 2. 九州大学病院検査部 Takahiro A. Kato¹, Toshio Matsushima¹, Sota Kyuragi¹, Keitaro Matsuo¹, Daiki Setoyama² 1. Dept. Neuropsychiatry, Grad.Sch.Med.Sci., Kyushu Univ., Fukuoka, Japan, 2. Dept. Clin. Chem. Lab. Med., Kyushu Univ. Hosp., Fukuoka, Japan Hikikomori is a crucial mental health problem. Biological basis of hikikomori has been unexplored. We have established the hikikomori-research system to understand multidimensional aspects of hikikomori based on bio-psycho-social analyses. Drug-free patients with hikikomori (n=42) and healthy controls (n=41) were recruited. The severity of hikikomori was assessed using the HQ-25. Blood biochemical tests and plasma metabolome analysis were performed. Based on the integrated information, machine-learning models were created to discriminate cases of hikikomori from healthy controls, predict hikikomori severity, stratify the cases, and identify metabolic signatures that contribute to each model. Long-chain acylcarnitine levels were remarkably higher in patients with hikikomori; bilirubin, arginine, ornithine, and serum arginase were significantly different in male patients with hikikomori. The discriminative random forest model was highly performant, exhibiting an area under the ROC curve of 0.854. To predict hikikomori severity, a partial least squares PLS-regression model was successfully created with high linearity and practical accuracy. Additionally, blood serum uric acid and plasma cholesterol esters contributed to the stratification of cases. Our findings reveal the blood metabolic signatures of hikikomori, which are key to elucidating the pathophysiology of hikikomori.