アルツハイマー病 2 Alzheimer's Disease 2
O1-8-4-1 common diseaseの遺伝学的解明：モデル動物とトランスクリプトミクスを組み合わせることでアルツハイマー病就職遺伝子としてKLC1のスプライシングヴァリアントを同定した An approach to complex diseases: combining model mice and transcriptomics reveals that splicing of KLC1 modifies Alzheimer's disease ○森原剛史1, 林紀行1, 横小路美貴子1木村展之5, 柳田寛太1, 赤津裕康2, 紙野晃人1, 鈴木利治4, 佐藤真広1, 田中稔久1, 武田雅俊1 ○Takashi Morihara1, Noriyuki Hayashi1, Mikiko Yokokoji1, Silverman Silverman3, Nobuyuki Kimura5, Kanta Yanagida1, Hiroyasu Akatsu2, Kojin Kamino1, Toshiharu Suzuki4, Masahiro Satoh1, Toshihisa Tanaka1, Masatoshi Takeda11 大阪大学1, 福祉村病院2, 北海道大学4, 基盤研5 Dept Psychiatry, Osaka University1, Choju Medical Institute, Fukushimura Hospital, Toyohashi-shi, Aichi, Japan2, Department of Biological Sciences, Simon Fraser University, Canada3, Hokkaido University, Laboratory of Neuroscience Graduate School of Pharmaceutical Sciences4, Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation5 Background: Alzheimer's disease (AD) is a common, complex neurological disease caused by numerous genetic and environmental factors making the identification of sporadic AD related genes difficult. To overcome these difficulties, we combined a mouse model of Abeta accumulation and transcriptomics, which simplifies the complexity, yet increases the statistical power for such a genetic screen.Methods: We prepared APP Tg mice with mixed genetic backgrounds by crossing onto three different strains, C57BL6 (B6), SJL and DBA/2 (DBA). The levels of Abeta in the cortex were measured by ELISA. The levels of mRNA in the hippocampus were measured using arrays, QPCR. SNPs in mice with mixed genetic background and human were analyzed. We also measured the total and splice variant E levels of KLC1 in human brain and lymphocyte.Results: Abeta accumulation levels in mice with DBA rich genetic backgrounds were drastically lower, less than one third of those in SJL or B6 rich genetic background. To identify the gene(s) which control Abeta accumulation, we performed transcriptomics in the mouse brains and identified kinesin light chain 1 (Klc1) splice variant E. QPCR analysis confirmed the correlation between the levels of Klc1 variant E and Abeta (R2=0.33, p<0.0001). Genomic analysis in Klc1 region also supported these findings. We examined whether the findings in mice can be translated to humans. We observed that the mRNA levels of KLC1 variant E were elevated in AD in both brain (+30.7%, p=0.0096) and lymphocyte (+25.0%, p=0.0013).Conclusion: We identified Klc1 splice variant E as a modifier of Abeta accumulation. The combination of model mice and transcriptomics is a powerful strategy which reveals a key molecule of neurological disease.	O1-8-4-2 認知症発症におけるγセクレターゼ及びその基質の機能解析を目的としたマウスモデル作製 Generation and analysis of mouse models to examine the roles of γ-secretase and its substrates on the pathogenesis of neurodegenerative dementia ○渡部博貴1 ○Hirotaka Watanabe1, Jin Zheng1, Mary Wines-Samuelson1, Jie Shen1 ハーバード・ブリガム病院・神経1 Dept Neurol, Brigham&Women's Hosp, Harvard Univ, Boston, US1 Mutations in the presenilin-1 (PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). We previously showed that forebrain-specific conditional inactivation of presenilins causes progressive neurodegeneration, indicating that presenilins are required for neuronal survival in the adult cerebral cortex. In this study, we first investigate whether Notch1 and/or Notch2 are functional targets of presenilin/γ-secretase in promoting neuronal survival in the adult cerebral cortex by generating Notch1, Notch2 and Notch1/Notch2 conditional knockout (cKO) mice. Unexpectedly we did not detect any neuronal degeneration in the adult cerebral cortex of these Notch cKO mice up to 2 years of age, whereas conditional inactivation of presenilins using the same αCaMKII-Cre transgenic mouse exhibits striking neuronal loss. These results conclude that Notch1 and Notch2 are not involved in the age-related neurodegeneration caused by loss of presenilin/γ-secretase, probably due to their negligible expression in pyramidal neurons of the adult cerebral cortex. We next investigate whether a dementia-related PSEN1 mutation exhibits loss-of-presenilin function in vivo by generating a knockin (KI) mice carrying a Psen1 c.548G>T mutation, originally identified in Belgian FTD pedigree. The resulting c.548G>T KI mice were viable but expressed markedly lower levels of presenilin-1 mRNA and protein in the brain due to aberrant splicing and subsequent degradation. Accordingly, γ-secretase activities were strongly reduced in the cerebral cortex of KI mice, as measured by in vitro γ-secretase cleavage assay. Furthermore, Psen1 c.548G>T KI/KI; Psen2-/- mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the PSEN1 c.548G>T mutation results in a brain-specific reduction of presenilin-1, supporting loss of presenilin function mechanism in the pathogenesis of Alzheimer's disease and related dementias.
O1-8-4-3 アミロイドベータによる長期増強の抑制にcollapsin response mediator protein 2のリン酸化が関与する Phosphorylation of collapsin response mediator protein 2 is involved in amyloid β-induced impairment of long-term potentiation ○磯野俊成1,2, 山下直也1, 紙谷義孝1, Alkam Tursun3, 新田淳美4, 鍋島俊隆3, 五嶋良郎1 ○Toshinari Isono1,2, Naoya Yamashita1, Yoshinori Kamiya1, Alkam Tursun3, Atsumi Nitta4, Toshitaka Nabeshima3, Yoshiro Goshima1 横市大院・医・分子薬理神経生物1, 横国大院・工・電子情報2, 名城大院・薬・薬品作用3, 富山大院・医薬・薬物治療4 Dept Mol Pharmacol Neurobiol, Yokohama City Univ Grad Sch Med, Yokohama, Japan1, Dept Electr Comput Eng, Yokohama National Univ Grad Sch Eng, Yokohama, Japan2, Dept Chem Pharmacol, Meijo Univ Grad Sch Pharmaceut Sci, Nagoya, Japan3, Dept Pharmaceut Therapy Neuropharmacol, Univ Toyama Grad Sch Med Pharmaceut Sci, Toyama, Japan4 Collapsin response mediator protein 2 (CRMP2) is an intracellular protein mediating Semaphorin3A, a repulsive axon guidance molecule. Amyloid-β (Aβ) protein is implicated in Alzheimer's disease (AD), and hyperphosphorylated CRMP2 as well as tau are accumulated in neurofibrillary tangles, a pathological hallmark of AD. We found that intracerebroventricular (i.c.v) injection of Aβ25-35 peptide, a neurotoxic fragment of Aβ protein, to mice increase the levels of phosphorylated CRMP2 in the brain. To investigate the role of the CRMP2 phosphorylation in the Aβ toxicity, we generated CRMP2 phosphorylation-deficient knock-in (CRMP2-KI) mice. Behavioral assessment revealed that i.c.v injection of β25-35 peptide caused impairment of novel object recognition in wild-type (WT) mice, but not in CRMP2-KI mice. We examined the electrophysiological characteristics of synaptic transmission efficiency in hippocampal slices. WT and CRMP2-KI mice have similar input-output basal synaptic transmission and paired-pulse ratios. The impairment of long-term potentiation (LTP) was observed in WT but not in CRMP2-KI slices applied with Aβ25-35 peptide. This result indicates that the CRMP2 phosphorylation is required for Aβ-induced impairment of hippocampal LTP.	O1-8-4-4 アルツハイマー型認知症患者におけるワーキングメモリ課題時の脳律動活動の変化について：MEGによる検討 Induced oscillatory power changes related with visual-object working memory dysfunction in patients with Alzheimer's disease and mild cognitive impairment: an MEG study ○石井良平1, 青木正典1, 池田俊一郎1, 畑真弘1, レオニデスカヌエト2, 岩瀬真生1, 数井裕光1, 武田雅俊1 ○Ryouhei Ishii1, Masanori Aoki1, Shunichirou Ikeda1, Masahiro Hata1, Leonides Canuet2, Masao Iwase1, Hiroaki Kazui1, Masatoshi Takeda1 大阪大学大学院医学系研究科精神医学1, マドリッド工科大学生体医工学センター2 Dept Psychiatry, Osaka Univ, Osaka1, Centre for Biomedical Technology (CTB), Technical University of Madrid (UPM), Madrid, Spain2 Magnetoencephalography was used to identify differences in induced oscillatory responses during a modified version of the Sternberg's memory recognition task performed by patients with early Alzheimer's disease (AD), mild cognitive impairment (MCI), and by age-matched healthy controls. The retention period of the working memory task was focused for MEG analysis. We used multiple-source beamformer and Brain Voyager to localize source-power changes across the cortex and for statistic group analyses, respectively. Significant differences in oscillatory response during the task, specifically in beta and gamma frequency bands was found in patients with AD, showing reduced beta event-related desynchronization (ERD) in the right central area compared to controls and reduced gamma ERD in the left prefrontal and medial parietal cortex compared to patients with MCI. Reduced oscillatory responses over certain brain regions in high frequency bands (i.e., beta, gamma), and especially in the beta band that was significantly different between AD patients and healthy subjects, may represent brain electromagnetic changes underlying visual-object working memory dysfunction in early AD, and a neurophysiological indicator of cognitive decline.

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