一般口演 (Oral Sessions)

アルツハイマー病 1 Alzheimer's Disease 1
O1-8-3-1 フェノール化合物は特異的結合によってAβオリゴマー形成及びシナプス毒性を抑制する Phenolic compounds prevent amyloid Aβ-protein oligomerization and synaptic dysfunction by site-specific binding ○小野賢二郎¹, , 高村雄策³, 吉池裕二⁴, 池田篤平¹, 西条寿夫³, 高島明彦⁴山田正仁¹ ○Kenjiro Ono¹, Lei Li², Yusaku Takamura³, Yuji Yoshiike⁴, Tokuhei Ikeda¹, Hisao Nishijo³, Akihiko Takashima⁴, David B. Teplow⁵, Michael G. Zagorski², Masahito Yamada¹ 金沢大学脳老化・神経病態学（神経内科）¹, ケースウエスタンリザーブ大学化学², 富山大学大学院システム情動科学³, 国立長寿医療研究センター研究所⁴, カリフォルニア大学ロサンゼルス校神経学⁵ Dept Neurol and Neurobiol Aging, Kanazawa University, Kanazawa¹, Dept Chem, Case Western Reserve University², Syst Emotion Sci, Univ of Toyama³, Res Inst, Nation Center for Geriat and Gerontol⁴, Dep Neurol, David Geffen School of Medicine at UCLA⁵ Cerebral deposition of amyloid β-protein (Aβ) is an invariant feature of Alzheimer disease (AD), and epidemiological evidence suggests that moderate consumption of foods enriched with phenolic compounds reduce the incidence of AD. We reported previously that the phenolic compounds myricetin (Myr) and rosmarinic acid (RA) inhibited Aβ aggregation in vitro and in vivo. To elucidate a mechanistic basis for these results, we analyzed the effects of five phenolic compounds in the Aβ aggregation process and in oligomer-induced synaptic toxicities. We now report that the phenolic compounds blocked Aβ oligomerization, and Myr promoted significant NMR chemical shift changes of monomeric Aβ. Both Myr and RA reduced cellular toxicity and synaptic dysfunction of the Aβ oligomers. These results suggest that Myr and RA may play key roles in blocking the toxicity and early assembly processes associated with Aβ through different binding.	O1-8-3-2 Diosgeninは1, 25D₃-MARRS(Pdia3/ERp57)の外因性の活性化因子として、5XFADマウスにおけるアルツハイマー病態を改善する Diosgenin is an exogenous activator of 1,25D₃-MARRS (Pdia3/ERp57) and improves memory dysfunction and axonal degeneration in Alzheimer's disease model 5XFAD mice ○東田千尋¹, 浦野卓矢¹, 梅嵜雅人², 久保山友晴¹ ○Chihiro Tohda¹, Takuya Urano¹, Masahito Umezaki², Tomoharu Kuboyama¹ 富山大学和漢医薬学総合研究所神経機能学分野¹, 富山大学和漢医薬学総合研究所民族薬物研究センター国際共同研究分野² Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama¹, Division of International Cooperative Research, Research Center for Ethnomedicine, Institute of Natural Medicine, Toyama² Diosgenin is a plant-derived famous steroidal sapogenin. Effects of Diosgenin on neurodegenerative diseases were not investigated. The aim of this study is to investigate the effects of Diosgenin on memory dysfunction in an Alzheimer's disease model, 5XFAD mice, and to identify the mechanism of Diosgenin especially a direct target protein.Diosgenin-treated (10 μmol/kg, i.p., 20 days) 5XFAD mice significantly showed improvement of object recognition memory. Diosgenin treatment significantly reduced burdens of amyloid plaques and neurofibrillary tangles in the cerebral cortex and hippocampus. Only in closely associated regions with amyloid plaques, abnormal structures of axons such as bulb-like endings and swollen presynaptic boutons were observed. These degenerated axons and presynaptic terminals were significantly reduced by Diosgenin treatment in the cerebral cortex and hippocampus. Using DARTS method, 1,25D₃-membrane-associated, rapid response steroid-binding (1,25D₃-MARRS) was shown as a direct target protein of Diosgenin. Cell surface binding of a physiological ligand of 1,25D₃-MARRS, 1α,25-dyhydroxyvitamin D3 was replaced by Diosgenin. 1,25D₃-MARRS knockdown completely inhibited Diosgenin-induced axonal growth in cultured cortical neurons. Treatment with neutralizing antibody against 1,25D₃-MARRS diminished axonal regeneration effect of Diosgenin against Aβ(1-42)-induced axonal atrophy.This is the first to report that Diosgenin recovered memory disorder in 5XFAD mice and restored axonal and presynaptic degenerations in the cerebral cortex and hippocampus. We also found that Diosgenin may work as an exogenous stimulator of 1,25D₃-MARRS and induces axonal growth and regrowth even in Aβ-induced damaging condition. These results suggest that 1,25D₃-MARRS pathway is activated by exogenous stimulator Diosgenin and may be very critical signaling for anti-AD.
O1-8-3-3 ヒトミトコンドリア転写因子TFAMの発現はアルツハイマー病モデルマウスの認知機能を改善する Expression of human mitochondrial transcriptional factor A (hTFAM) improves cognitive function in Alzheimer's disease model mice ○岡素雅子¹, 康東天², 中別府雄作¹ ○Sugako Oka¹, Dongchon Kang², Yusaku Nakabeppu¹ 九州大学　生体防御医学研究所　脳機能制御学分野, ヌクレオチドプール研究センター¹, 九州大学医学研究院臨床検査医学分野² Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and Research Center for Nucleotide Pool, Kyushu University¹, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University² Mitochondrial dysfunction is considered to have a pivotal role for developing Alzheimer's disease (AD). It has been reported that amyloid β (Aβ) accumulated in cytoplasm induce mitochondrial dysfunction and ROS production by interacting with Aβ-binding alcohol dehydrogenase, mitochondrial matrix components. It has been reported that 8-oxoguanine (8-oxoG), one of the major oxidation products in DNA/RNA and nucleotides, accumulates in AD brain. Oxidative DNA damage especially in mitochondrial DNA can lead to synaptic dysfunction and neuronal loss, and thereby causing neurodegenation. In the present study, we examined effects of human mitochondrial transcriptional factor A (hTFAM) transgene on the pathology of a mouse model of AD (3xTg-AD) harboring PS1M146V, APP(Swe), and tauP301L transgenes. TFAM is now known to contribute not only in transcription of mitochondrial DNA but also maintenance of mitochondrial DNA, and thus protecting mitochondria from oxidative stress. In the Morris Water Maze test, 13-month-old 3xTg-AD hemizygous mice carrying hemizygous hTFAM transgene exhibited significant improvement of learning and memory deficit compared to 3xTgAD hemizygous mice without the hTFAM transgene. Accumulation of Aβ was markedly decreased in cerebral cortices and hippocampi of the 3xTg-AD/hTFAM hemizygous mice. Moreover, 3xTg-AD/hTFAM hemizygous mice exhibited much less 8-oxo-dG immunoreactivity in cerebral cortices and hippocampi in comparison to 3xTgAD hemizygous mice which accumulated higher level of 8-oxo-dG in axonal mitochondria. To clarify the mechanism of improvement of AD phenotype by hTFAM, we are currently performing gene expression profiling using hippocampal RNA prepared from these animals. These results will provide the new insight to understand the molecular mechanisms of AD pathology and possible new strategies for the therapy of AD.	O1-8-3-4 アルツハイマー病におけるアストロサイトからのIGFBPの関与 The relationship between IGFBP released from astrocyte and Alzheimer's disease ○渡邉究¹, 植村健吾¹, 浅田めぐみ², 前迫真人², 上田かりん², 上村麻衣子¹, 久保田正和², 木原武士³, 秋山治彦⁴, 下濱俊⁵, 高橋良輔¹, 木下彩栄² ○Kiwamu Watanabe¹, Kengo Uemura¹, Megumi Asada², Masato Maesako², Karin Ueda², Maiko Uemura¹, Masakazu Kubota², Takeshi Kihara³, Haruhiko Akiyama⁴, Syun Shimohama⁵, Ryosuke Takahashi¹, Ayae Kinoshita²² 京都大学大学院　医学部　臨床神経学¹, 京都大学大学院　医学部　人間健康科学², 洛和会　みささぎ病院³, 東京都医学総合研究所⁴, 札幌医科大学　神経内科⁵ Dept Neurology, Kyoto Univ, Kyoto, Japan¹, School of human health sciences faculty of medicine, Kyoto Univ, Kyoto, Japan², Misasagi Hospital, Kyoto, Japan³, Tokyo metropolitan institute of medical science, Tokyo, Japan⁴, Dept of neurology, Sapporo medical Univ⁵ Activation of glial cells is a well-known pathological feature of Alzheimer's disease (AD). Cytokines and/or some factors released from activated glial cells might induce neuronal damage. On the other hand, it has been suggested that insulin-like growth factor (IGF) binding protein (IGFBP) is involved in the pathology of AD. For example, it was reported that the concentration of cerebrospinal fluid (CSF) and serum IGFBPs in the patients with AD is higher than in normal control. IGFBP can induce cell apoptosis by IGF dependent or independent manner. On the contrary, IGFBP can conduce to cell survival by cooperating with IGF. Thus, in the present study, we focus on IGFBP released from glial cells, especially astrocytes, and investigated how IGFBP affects the pathology of AD. We examined change of mRNA and protein expression of IGFBP by RT-PCR and Western blotting using human astrocytoma cell lines (H4) treated by amyloid beta-peptide (Aβ42). We found that mRNA and expression of IGFBP were increased intra- and extra-cellularly when H4 was treated by Aβ. This increase of IGFBP was inhibited by FK506, a calcineurin inhibitor. An increase of IGFBP was also suggested in AD brains. We also checked the effect of IGFBP on IGF signal.Thus, we concluded that IGFBP released from glial cells might be involved in AD pathology, and could gain a new therapeutic target of AD

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