若手道場

若手道場アルツハイマー病

7月6日（木）　17:30-18:30　Room H 1W⑧-1 tRNA断片を介した神経細胞内タウ蛋白凝集の誘導と凝集体細胞間伝播メカニズムの解明 tRNA fragments as aggregation and propagation factor of tau pathology in neurodegenerative diseases 小林　天美¹ 1. ハーバード医科大学附属ブリガム・アンド・ウィメンズ病院　脳神経内科, 2. ハーバード医科大学附属ベス・イスラエル・ディーコネス病院　脳神経内科 Ami Kobayashi¹ 1. Dept. of Neurology., Brigham and Women's Hospital, Harvard Medical School, Boston, USA, 2. Beth Israel Deaconess Hospital, Harvard Medical School, Boston, USA Alzheimer's disease (AD) is characterized by neuronal damage caused by abnormal tau aggregation and deposition after chronic stress. Tau aggregates are transmitted between cells, resulting in the expansion of tau deposits in the brain. RNA, particularly stress-induced tRNA-derived fragments (tiRNAs) have been shown to bind with tau, suggesting their role in tauopathies including AD. In this study, we observed elevated levels of specific tiRNAs in the hippocampus of PS19 mice, a human tau protein aggregation model, and AD patients. Both intracellular and extracellular compartments in primary rat neurons showed an increase in the specific tiRNA, 5’-GluCTC, along with increased tau complexes under sustained stress condition. Immunofluorescence in situ hybridization showed co-localization and changes in intracellular tau aggregates and 5’-GluCTC. Furthermore, 5’-GluCTC was elevated in both primary neurons cultured with conditioned media from stressed cells and PS19 mice cells, suggesting the uptake from the extracellular compartment. This also correlated with increased expression levels of tau complexes and visualized tau aggregates. Our study suggests that specific tiRNA may be a crucial factor in both tau aggregation and the intercellular transmission of aggregates. It can be an innovative target for developing prophylactic and therapeutic strategies against tauopathies.		7月6日（木）　17:30-18:30　Room H 1W⑧-2 生理的条件下における遊離型タウ結合因子の同定 Identification of factors that bound to physiological free tau: implication for endogenous suppressor of tau aggregation 辰本　彩香^1,2, 渡邉　淳³, 宮坂　知宏^1,2 1. 同志社大学大学院　生命医科学研究科　神経病理学研究室, 2. 同志社大学神経変性疾患研究センター, 3. 国立長寿医療研究センター Ayaka Hagita-Tatsumoto^1,2, Atsushi Watanabe³, Tomohiro Miyasaka^1,2 1. Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan, 2. Center for Research in Neurodegenerative Diseases, Doshisha University, Kyoto, Japan, 3. National Center for Geriatrics and Gerontology, Aichi, Japan Neurofibrillary tangles (NFTs), pathological inclusions of tau protein, are found in the brains of Alzheimer's disease (AD). Because the site and frequency of NFTs are correlated with those of neuron loss, suppression of NFT formation is a promising therapeutic strategy for AD. NFT-forming tau have lost their ability to bind to microtubules (MTs) and aggregate by its MT-binding domain (MTBD). Therefore, tau liberated from MTs with its MTBD exposed is considered to be involved in the NFT formation. More than 10% of total tau was unbound to MTs even in wild-type (WT) mouse brains. However, biochemical analyses suggested that such free tau in healthy brain form complex with unknown factors. Thus, it is possible that the physiological free tau (FT) is protected from pathological aggregation by its interactors. To identify the interactors of non-pathological FT, we fractioned and immunoprecipitated FT from the brains of P301S tau knock-in (PSKI) and transgenic mice, which are incompetent and competent to form tau pathologies respectively. SDS-PAGE followed by silver stating indicated numerous co-precipitated proteins found only in FT from PSKI mice. LC-MS analyses identified several proteins as multiple candidates for FT interactors. Now we evaluate those ability to bind on MTBD and to inhibit tau aggregation and whether the knockdown of candidates deteriorates NFT formation.

7月6日（木）　17:30-18:30　Room H 1W⑧-3 Altered brain energy metabolism related to astrocytes in Alzheimer's disease 平田　浩聖¹, 高堂　裕平^1,3, 松岡　究¹, 互　健二¹, 遠藤　浩信¹, 建部　陽嗣¹, 小野　麻衣子¹, 小久保　奈緒美¹, 篠遠　仁¹, 高畑　圭輔¹, 小畠　隆行¹, 河村　和紀¹, 張　明栄¹, 島田　斉⁴, 横田　隆徳², 徳田　隆彦¹, 樋口　真人¹ 1. 量子科学技術研究開発機構　量子医科学研究所, 2. 東京医科歯科大学　脳神経病態学分野(脳神経内科), 3. 量子科学技術研究開発機構　量子生命科学研究所, 4. 新潟大学脳研究所附属統合脳機能研究センター Kosei Hirata¹, Yuhei Takado^1,3, Kiwamu Matsuoka¹, Kenji Tagai¹, Hironobu Endo¹, Harutsugu Tatebe¹, Maiko Ono¹, Naomi Kokubo¹, Hitoshi Shinotoh¹, Keisuke Tkahata¹, Takayuki Obata¹, Kazunor Kawamura¹, Ming-Rong Zhang¹, Hitoshi Shimada⁴, Takanori Yokota², Takahiko Tokuda¹, Makoto Higuchi¹ 1. Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 2. Department of Neurology and Neurological Science, Tokyo Medical and Dental University, 3. Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4. Center for Integrated Human Brain Science, Brain Research Institute, Niigata University [Objective] Increasing evidence suggests that astrocytes are associated with Alzheimer’s disease (AD). Given the role of astrocytes in energy metabolism, astrocytes may contribute to altered energy metabolism. It is hypothesized that lactate is produced in astrocytes and subsequently shuttled to neurons as an energy substrate. We aimed to assess changes in brain lactate levels and their association with astrocytic activities in AD. [Methods] 30 AD and 30 cognitively unimpaired (CU) subjects were enrolled. Lactate and myo-inositol (mI), an astroglial marker, in the posterior cingulate cortex (PCC) were measured by magnetic resonance spectroscopy (MRS). Plasma biomarkers were also assessed including GFAP as another astrocytic marker. This study was approved by the Ethics Committee. [Results] Lactate and mI levels were higher in AD compared to CU group (p＜0.05). Lactate levels correlated with mI levels (r=0.272, p＜0.05). Lactate and mI levels showed a correlation with the CDR sum-of-boxes score (p＜0.05). There was a positive association between mI and plasma GFAP levels (p＜0.05). [Conclusion] We found elevated lactate levels accompanied by an increased astroglial marker in the PCC in AD. It suggested that the impaired lactate shuttle of astrocytes disrupts energy utilization, resulting in surplus of lactate. MI and plasma GFAP may reflect similar changes in astrocytes.		7月6日（木）　17:30-18:30　Room H 1W⑧-4 Diosgeninによる脳内での軸索再伸長の鍵となる転写因子の探索 Exploration of key transcription factors for diosgenin-induced axonal regeneration in the brain. 永田　朋也, 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 Tomoya Nagata, Ximeng Yang, Chihiro Tohda Sec. of Neuromedical Science, Inst. of Natural Medicine, Univ. of Toyama, Japan Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of Aβ. Our therapeutic strategy for AD is to reconstruct neural circuits in the brain. We previously found that diosgenin promoted long-distance axonal regeneration toward to their accurate projection brain areas and recovered memory deficits in AD model (5XFAD) mouse. Importantly, the expression level of many proteins in neurons that contributed to axonal regeneration were precisely regulated by diosgenin. The present study aimed to explore candidates of transcription factors to regulate the expression of these proteins required for direction-specific axonal regeneration. Axonal growth in cultured hippocampal neurons (ddY mice, P7) was significantly promoted after 3-, 5-, 7-, and 9-day treatments of diosgenin (1 μM) compared with vehicle solution. Since the velocity of axonal growth was peaked after 7-day-treatment of diosgenin, the RNA was extracted to perform RNA-seq. In significantly changed 4274 genes, the most upregulated gene, which has been recognized as a transcription factor, was identified as Rn7sk. We are now investigating effects of Rn7sk overexpression on axonal regeneration, memory recovery, and regulating expression of proteins for diosgenin-induced axonal regeneration. This study would demonstrate a key regulator for direction-specific axonal regeneration in the brains.