Development of therapy targeting amyloid β protein oligomer in lipid rafts

2008 Fiscal Year Final Research Report

• Project/Area Number: 19590976
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Hirosaki University
• Principal Investigator: KAWARABAYASHI Takeshi Hirosaki University, 医学部附属病院, 講師 (90186156)
• Co-Investigator(Kenkyū-buntansha): SHOJI Mikio 弘前大学, 大学院・医学研究科, 教授 (60171021) ; WATANABE Mitsunori 弘前大学, 医学部附属病院, 助教 (90251107)
• Co-Investigator(Renkei-kenkyūsha): ETSURO Matsubara 弘前大学, 大学院・医学研究科, 准教授 (70219468)
• Project Period (FY): 2007 – 2008
• Keywords: 神経分子病態学 / リピドラフト / オリゴマー / アミロイド / アルツハイマー病

Research Abstract

神経変性疾患モデルを用いてlipid raftsでのオリゴマー蓄積を検討した. 1. 培養細胞ではlipid rafts の蛋白の変化がAs前駆体の分布を変化させた, 2. APP発現マウスに高コレステロール食を投与すると脳Asの増加と共に脳lipid rafts分画中へのAsオリゴマーが増加した. 3. Tau発現マウスでは初期からtauが脳lipid raftsに高濃度に存在し, 加齢と共に増加しオリゴマーも認められた, 4. 新たに作成したα-synuclein発現マウスでも脳lipid raftsへのα-synuclein蓄積の増加を認めた, Lipid raftsは蛋白凝集体蓄積の共通開始部位であることが示された, lipid raftsにおけるオリゴマー制御は神経変性疾患の根本的治療法になりうると考えられた.

Research Products

• [Journal Article] Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese (2009)
  • Author(s): Kuwano R, Takei N, Miyashita A, Tsukie T, Arai H, Asada T, Imagawa M, Shoji M, Higuchi S, Urakami K, Kimura H, Kakita A, Takahashi H, Tsuji S, Kanazawa I, Ihara Y, Odani S, Kuwano R.
  • Journal Title: Genomics 93 Pages: 441-448
  • Peer Reviewed
• [Journal Article] A chemical chaperone, sodium 4-phenyl butyric acid, attenuates the pathogenic potency in human α-synuclein A30P+A53T transgenicmice. Parkinsonism Relat Disord (2009)
  • Author(s): Ono K, Ikemoto M, Kawarabayashi T, Ikeda M, Nishinakagawa T, Hosokawa M, Shoji M, Takahashi M, Nakashima M
  • Journal Title: Epubahead of print
  • Peer Reviewed
• [Journal Article] An unusual case of chronic relapsing tetanus associated with mandibular osteomyelitis (2009)
  • Author(s): Wakasaya Y, Watanabe M, Tomiyama M, Suzuki C, Jackson M, Fujimuro M, Kimura T, Seino Y, Kawarabayashi T, Yamamoto-Watanabe Y, Matsubara E, Shirahama I, Takamura A, Nakahata N, Shoji M
  • Journal Title: Intern Med, Epubahead of print
  • Peer Reviewed
• [Journal Article] Motor impairment and aberrant production of neurochemicals in human α-synuclein A30P+A53T transgenic mice with α-synuclein pathology (2009)
  • Author(s): Ikeda M, Kawarabayashi T, Harigaya Y, Sasaki A, Yamada S, Matsubara E, Murakami T, Tanaka Y, Kurata T, Wuhua X, Ueda K, Kuribara H, Ikarashi Y, Nakazato Y, Okamoto K, Abe K, Shoji M
  • Journal Title: Brain Res. 1250 Pages: 232-241
  • Peer Reviewed
• [Journal Article] GAB2 is not associated with late-onset Alzheimer's disease in Japanese (2009)
  • Author(s): Miyashita A, Arai H, Asada T, Imagawa M, Shoji M, Higuchi S, Urakami K,Toyabe S, Akazawa K, Kanazawa I, Ihara Y, Kuwano R
  • Journal Title: Eur J Hum Genet 17 Pages: 682-686
  • Peer Reviewed
• [Journal Article] Transthyretin accelerates vascular Aβ deposition in a mouse model of Alzheimer's disease (2009)
  • Author(s): Wati H, Kawarabayashi T, Matsubara E, Kasai A, Hirasawa T, Kubota T, Harigaya Y, Shoji M, Maeda S
  • Journal Title: Brain Pathol 19 Pages: 48-57
  • Peer Reviewed
• [Journal Article] Plasma biomarkers of Alzheimer's disease (2008)
  • Author(s): Kawarabayashi T, Shoji M
  • Journal Title: Curr Opin Psychiatry 21 Pages: 260-267
• [Journal Article] Microglial activation in brain lesions with tau deposits : comparison of human tauopathies and tau transgenic mice TgTauP301L (2008)
  • Author(s): Sasaki A, Kawarabayashi T, Murakami T, Matsubara E, Ikeda M, Hagiwara H, Westaway D, St. George-Hyslop P, Shoji M, Nakazato Y
  • Journal Title: Brain Res 1214 Pages: 260-267
  • Peer Reviewed
• [Journal Article] Plasma antibodies to Abeta40 and Abeta42 in patients with Alzheimer's disease and normal controls (2008)
  • Author(s): Xu W, Kawarabayashi T, Matsubara E, Deguchi K, Murakami T, Harigaya Y, Ikeda M, Amari M, Kuwano R, Abe K, Shoji M
  • Journal Title: Brain Res 121 Pages: 169-179
  • Peer Reviewed
• [Journal Article] Differentiation of PA from early PSP with different patterns of symptoms and CBF reduction (2008)
  • Author(s): Kurata T, Hayashi T, Murakami T, Miyazaki K, Morimoto N, Ohta Y, Takehisa Y, Nagai M, Kawarabayashi T, Takao Y, Ohta T, Harigaya Y, Manabe Y, Kamiya T, Shoji M, Abe K.
  • Journal Title: Neurol Res 30 Pages: 860-867
  • Peer Reviewed
• [Journal Article] A small trinucleotide expansion in the TBP gene gives rise to a sporadic case of SCA17 with abnormal putaminal findings on MRI (2008)
  • Author(s): Watanabe M, Monai N, Jackson M, Yamamoto-Watanabe Y, Ikeda Y, Suzuki C, Tomiyama M, Kawarabayashi T, Kimura T, Seino Y, Wakasaya Y, Miki Y, Matsubara E, Shoji M
  • Journal Title: Intern Med 47 Pages: 2179-2182
  • Peer Reviewed
• [Journal Article] Exacerbation of chronic pancreatitis induced by anticholinesterase medications in myasthenia gravis (2008)
  • Author(s): Tomiyama M, Arai A, Kimura T, Suzuki C, Watanabe M, Kawarabayashi T, Shoji M
  • Journal Title: Eur J Neurol 15 Pages: e40-41
  • Peer Reviewed
• [Journal Article] Reuptake of L-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson's disease via norepinephrine transporter (2008)
  • Author(s): Arai A, Tomiyama M, Kannari K, Kimura T, Suzuki C, Watanabe M, Kawarabayashi T, Shen H, Shoji M
  • Journal Title: Synapse 62 Pages: 632-635
  • Peer Reviewed
• [Journal Article] A Novel Mutation in the Arylsulfatase A Gene Associated with Adult-Onset Metachromatic Leukodystrophy without Clinical Evidence of Neuropathy (2008)
  • Author(s): Suzuki C, Watanabe M, Tomiyama M,Sugimoto K, Nanba E, Jackson M, KimuraT, Seino Y, Wakasaya Y, KawarabayashiT, Miki Y, Yamamoto-Watanabe Y, Shoji M
  • Journal Title: Eur Neurol 60 Pages: 310-311
  • Peer Reviewed
• [Journal Article] Sendai virus-mediated gene transfer of GDNF reduces AIF translocation and ameliorates ischemic cerebral injury (2008)
  • Author(s): JJin G、Inoue M、Hayashi T、Deguchi K、Nagotani S、Zhang H、Wang X、Shoji M, Hasegawa M 、Abe K
  • Journal Title: Neurol Res 30 Pages: 731-739
  • Peer Reviewed
• [Journal Article] Enhanced accumulation of phosphorylated α-synuclein in double transgenic mice expressing mutant βAPP and presenilin-1 (2007)
  • Author(s): Kurata T, Kawarabayashi T, Murakami T, Miyazaki K, Morimoto N, Ohta Y, Takehisa Y, Nagai M, Ikeda M, Matsubara E, Westaway D, St.George-Hyslop P, Harigaya Y, Kamiya T, Shoji M, Abe K
  • Journal Title: J Neurosci Res 85 Pages: 2246-2252
  • Peer Reviewed
• [Journal Article] a gene product of PARK6, accumulates in α-synucleinopathy brains (2007)
  • Author(s): Murakami T, Moriwaki Y, Kawarabayashi T, Nagai M, Ohta Y, Deguchi K, KurataT, Takehisa Y, Matsubara E, Ikeda M, Harigaya Y, Shoji M, Takahashi R, Abe K, PINK1
  • Journal Title: J Neurol Neurosurg Psychiatry 78 Pages: 653-654
  • Peer Reviewed
• [Journal Article] The Japanese Genetic Study Consortium for Alzheimer's Disease, Consortium Information: Members are listed in the cknowledgements. Genetic association of CTNNA3 with late-onset Alzheimer's disease in females (2007)
  • Author(s): Miyashita A, Arai H, Asada T, Imagawa M, Matsubara E, Shoji M, Higuchi S, Urakami K, Kakita A, Takahashi H, Toyabe S, Akazawa K, Kanazawa I, Ihara Y, Kuwano R
  • Journal Title: Hum Mol Genet 16 Pages: 2854-2869
  • Peer Reviewed
• [Journal Article] Increased ER stress during motor neuron degeneration in a transgenic mouse model of amyotrophic lateral sclerosis (2007)
  • Author(s): Nagata T, Ilieva H, Murakami T, Shiote M, Narai H, hta Y, Hayashi T, Shoji M,Abe K.
  • Journal Title: Neurol Res 29 Pages: 767-771
  • Peer Reviewed
• [Journal Article] Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients (2007)
  • Author(s): Nagata T, Nagano I, Shiote M, Narai H, Murakami T, Hayashi T, Shoji M, Abe K
  • Journal Title: Neurol Res 29 Pages: 772-776
  • Peer Reviewed
• [Journal Article] Induction of platelet derived-endothelial cell growth factor in the brain after ischemia (2007)
  • Author(s): Hayashi T, Wang XQ, Zhang HZ, Deguchi K, Nagotani S, Sehara Y, Tsuchiya A, Nagai M, Shoji M, Abe K
  • Journal Title: Neurol Res 29 Pages: 463-468
  • Peer Reviewed
• [Journal Article] A ganglioside-induced toxic soluble As assembly. Itβ enhanced formation from Aβ bearing the Arctic mutation (2007)
  • Author(s): Yamamoto N, Matsubara E, Maeda S, Minagawa H, Takashima A, Maruyama W, Michikawa M, Yanagisawa K
  • Journal Title: J Biol Chem 282 Pages: 2646-2655
  • Peer Reviewed
• [Journal Article] A unique case of limb-girdle muscular dystrophy type 2A carrying novel compound heterozygous mutations in the human CAPN3 gene (2007)
  • Author(s): Matsubara E, Tsuchiya A, Minami N,Nishino I, appolla MA, Shoji M, Abe K.
  • Journal Title: Eur J Neurol 14 Pages: 819-822
  • Peer Reviewed
• [Journal Article] Two cases of spinocerebellar ataxia accompanied by involvement of the skeletal motor neuron system and bulbar palsy (2007)
  • Author(s): Ohta Y, Hayashi T, Nagai M, Okamoto M, Nagotani S, Nagano I, Ohmori N, Takehisa Y, Murakami T, Shoji M, Kamiya T, Abe K.
  • Journal Title: Intern Med 46 Pages: 751-755
  • Peer Reviewed
• [Journal Article] Asian origin for the worldwide-spread mutational event in Machado-Joseph disease (2007)
  • Author(s): Martins S, Calafell F, Gaspar C, Wong VC, Silveira I, Nicholson GA, Brunt ER, Tranebjaerg L, Stevanin G, Hsieh M, Soong BW, Loureiro L, Durr A, Tsuji S, Watanabe M, Jardim LB, Giunti P, Riess O, Ranum LP, Brice A, Rouleau GA, Coutinho P, Amorim A, Sequeiros J.
  • Journal Title: Arch Neurol 64 Pages: 1502-1508
  • Peer Reviewed
• [Journal Article] Familial amyloid polyneuropathy(Finnish type)in a Japanese family Clinical features and immunocytochemical studies (2007)
  • Author(s): Ikeda M, Mizushima K, Fujita Y, Watanabe M, Sasaki A, Makioka K, Enoki M, Nakamura M, Otani T, Takatama M, Okamoto K.
  • Journal Title: J Neurol Sci 252 Pages: 4-8
  • Peer Reviewed
• [Presentation] Accumulation of protein in lipid rafts in mouse models of neurodegenerative diseases (2009)
  • Author(s): Kawarabayashi T, Seino Y, Wakasaya Y, Takamura A, Nakahata N, Watanabe Y, Watanabe M, Matsubara E, Shoji M
  • Organizer: 11th Meeting of Hirosaki International Forum of Medical Science
  • Place of Presentation: Hirosaki
  • Year and Date: 2009-05-29
• [Presentation] CSF tau correlates with brain tau in tau transgenic mice (2008)
  • Author(s): Kawarabayashi T, Seino1Y, Wakasaya1Y, Watanabe M, Kimura1T, Suzuki C, Tomiyama M, Matsubara E, Ishiguro K, Westaway D, St.George-Hyslop P, Shoji M
  • Organizer: ICAD2008
  • Place of Presentation: Chicago
  • Year and Date: 2008-07-28
• [Presentation] Cortical neuronal and glial pathology in TgTauP301L transgenic mice the Society for Neuroscience (2007)
  • Author(s): Kawarabayashi T, Seino Y, Wakasaya Y, Watanabe M, Suzuki C, Tomiyama M, Matsubara E, Egashira N, Takahashi M, Fujiwara M, Carlson GA, Westaway D, St.George-Hyslop P, Shoji M
  • Organizer: 37^<th> Annual Meeting
  • Place of Presentation: San Diego
  • Year and Date: 20071103-7
• [Presentation] Characterization of therapeutic antibody against Aβ oligomers for Alzheimer's disease. the Society for Neuroscience (2007)
  • Author(s): Sun H, Okamoto Y, Kawarabayashi T, Yokoseki T, Shibata M, Morishima M, Saito Y, Murayama S, Ihara Y, Shoji M, Michikawa M, Matsubara E
  • Organizer: 37^<th> Annual Meeting
  • Place of Presentation: San Diego
  • Year and Date: 20071103-7
• [Presentation] Analysis of phosphorylation of tau in transgenic mice overexpressing GSK-3β. the Society for Neuroscience (2007)
  • Author(s): Ikeda M, Goris I, Sasaki A, Kawarabayashi T, Harigaya Y, Shoji M, Moechars D, Okamoto K
  • Organizer: 37th Annual Meeting
  • Place of Presentation: San Diego
  • Year and Date: 20071103-7
• [Presentation] Analysis of transgenic mice overexpressing mutant tau and GSK-3β (2007)
  • Author(s): Ikeda M, Goris I, Sasaki A, Kawarabayashi T, Ishiguro K, Shoji M, Harigaya Y, Westaway D, St George-Hyslop P, Moechars D, Okamoto K
  • Organizer: IPA 2007 Osaka Silver Congress of the International Psychiatrics Association
  • Place of Presentation: Osaka
  • Year and Date: 20071017-18
• [Presentation] Components of Lewy bodies (2007)
  • Author(s): Shoji M
  • Organizer: IPA 2007 Osaka Silver Congress of the International Psychiatrics Association
  • Place of Presentation: Osaka
  • Year and Date: 20071017-18
• [Presentation] Analysis of amyloid angiopathy in Tg2576 Transgenic mouse model of Alzheimer's disease (2007)
  • Author(s): Kawarabayashi T, Seino Y, Wakasaya Y, Kimura T, Suzuki C, Tomiyama M, Matsubara E, Shoji M
  • Organizer: The 23^<rd> International Synmpsium on Cerebralk Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka
  • Year and Date: 20070520-24
• [Presentation] As oligomer : An essential therapeutic target for Alzheimer's disease (2007)
  • Author(s): Shoji M
  • Organizer: The 23^<rd> International Synmpsium on Cerebralk Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-22
• [Book] MCIと認知症-リスクファクター- Annual Review 2009 神経(柳澤信夫, 篠原幸人, 岩田誠, 清水輝夫, 寺本明編) (2009)
  • Author(s): 瓦林毅, 東海林幹夫
  • Publisher: 中外医学社
• [Book] アルツハイマー病.神経疾患最新の治療(小林祥泰, 水澤英洋) (2009)
  • Author(s): 東海林幹夫
  • Publisher: 南江堂, 東京
• [Book] Alzheimer 病のバイオマーカー(岩坪威編別冊) (2007)
  • Author(s): 瓦林毅, 東海林幹夫
  • Publisher: 医学のあゆみ 医歯薬出版株式会社
• [Book] アルツハイマー病. 神経難病のすべて~症状・診断から最先端治療福祉の実際まで(阿部康二) (2007)
  • Author(s): 瓦林毅, 東海林幹夫
  • Publisher: 新興医学
• [Remarks]
  • URL: http://www.med.hirosaki-u.ac.jp/~neurology/study02.html
• [Patent(Industrial Property Rights)] ワクチンを蓄積する形質転換ダイズ植物およびその利用 (2008)
  • Inventor(s): 寺川輝彦, 長谷川久和, 石本政男, 内海成, 東海林幹夫, 瓦林毅
  • Industrial Property Rights Holder: 北興化学工業株式会社, 独立行政法人農業・食品産業技術総合研究機構, 国立大学法人京都大学, 国立大学法人弘前大学
  • Industrial Property Number: 特許願,特願2008-304006
  • Filing Date: 2008-11-28
• [Patent(Industrial Property Rights)] パーキンソン病モデルトランスジェニックマウス (2008)
  • Inventor(s): 東海林幹夫, 池田将樹, 山田秀一
  • Industrial Property Rights Holder: 北興化学工業株式会社, 独立行政法人農業・食品産業技術総合研究機構, 国立大学法人京都大学, 国立大学法人弘前大学
  • Industrial Property Number: 特許,第4174212号
  • Acquisition Date: 2008-08-22