Development and clinical application of novel methods for diagnosis and therapy of Alzheimer disease by regulation of neurotoxic oligomer

2009 Fiscal Year Final Research Report

• Project/Area Number: 19390233
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Hirosaki University
• Principal Investigator: SHOJI Mikio Hirosaki University, 大学院・医学研究科, 教授 (60171021)
• Co-Investigator(Kenkyū-buntansha): MATSBARA Etsuro 弘前大学, 大学院・医学研究科, 准教授 (70219468) ; KAWARABAYASHI Takeshi 弘前大学, 附属病院, 講師 (90186156) ; WATANABE Mitsunori 弘前大学, 附属病院, 助教 (90251107)
• Project Period (FY): 2007 – 2009
• Keywords: 神経病態生化学

Research Abstract

Recent studies suggest that oligomers are direct pathogenic agents to cause synaptic and neuronal disturbance in dementia patients including Alzheimer's disease. In this study, we established special antibodies to Ass, tau and α-synuclein to develop ELISA and detection systems, showing soluble oligomers, naturally occurred anti-Ass antibodies in brains and CSF in AD patients. Model mice of DLB (TgSNY) and AD (2xTgTau+/-APP+/-) were established. The pathological cascades of Ass induced tauopathy using 2xTgTau+/-APP+/- and NFT formation and neuronal cell deaths using by micro arrays were elucidated. Many biological pathways involved in these final cascades. Administration of anti-Ass antibodies reduced Ass burden and Ass oligomer in mice brains and increased in Ass monomer in CSF and plasma. Thus, anti-oligomer therapy is a possible agent for cure of neurodegenerative dementia.

Research Products

• [Journal Article] Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy (2010)
  • Author(s): Hirohata M, Yoshita M, Ishida C, Ikeda S-I, Tamaoka A, Kuzuhara S, Shoji M, Ando Y, Tokuda T, Yamada M
  • Journal Title: European Journal of Neurology
  • Peer Reviewed
• [Journal Article] Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans (2010)
  • Author(s): Perkins EM, Clarkson YL, Sabatier N, Longhurst DM, Millward CP, Jack J, Toraiwa J, Watanabe M, Rothstein JD, Lyndon AR, Wyllie DJ, Dutia MB, Jackson M
  • Journal Title: J Neurosci 30(14) Pages: 4857-67
  • Peer Reviewed
• [Journal Article] Japanese Genetic Study Consortium for Alzheimer Disease. Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese (2009)
  • Author(s): 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 63 Pages: 441-8
  • Peer Reviewed
• [Journal Article] Ataxia with oculomotor apraxia type 2 : clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients (2009)
  • Author(s): Anheim M, Monga B, Fleury M, Charles P, Barbot C, Salih M, Delaunoy JP, Fritsch M, Arning L, Synofzik M, Schols L, Sequeiros J, Goizet C, Marelli C, Le Ber I, Koht J, Gazulla J, De Bleecker J, Mukhtar M, Drouot N, Ali-Pacha L, Benhassine T, Chbicheb M, M'Zahem A, Hamri A, Chabrol B, Pouget J, Murphy R, Watanabe M, Coutinho P, Tazir M, Durr A, Brice A, Tranchant C, Koenig M
  • Journal Title: Brain 132(Pt 10) Pages: 2688-98
  • Peer Reviewed
• [Journal Article] A chemical chaperone, sodium 4-phenylbutyric acid, attenuates the pathogenic potency in human alpha-synuclein A30P+A53T transgenic mice (2009)
  • Author(s): Ono K, Ikemoto M, Kawarabayashi T, Ikeda M, Nishinakagawa T, Hosokawa M, Shoji M, Takahashi M, Nakashima M
  • Journal Title: Parkinsonism Relat Disord 15(9) Pages: 649-54
  • Peer Reviewed
• [Journal Article] Motor impairment and aberrant production of neurochemicals in human alpha-synuclein A30P+A53T transgenic mice with alpha-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: 232-41
  • 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(5) Pages: 682-6
  • Peer Reviewed
• [Journal Article] Transthyretin accelerates vascular Abeta 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(1) Pages: 48-57
  • 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(8) Pages: 860-7
  • Peer Reviewed
• [Journal Article] Sendai virus-mediated gene transfer of GDNF reduces AIF translocation and ameliorates ischemic cerebral injury (2008)
  • Author(s): Jin G, Inoue M, Hayashi T, Deguchi K, Nagotani S, Zhang H, Wang X, Shoji M, Hasegawa M, Abe K
  • Journal Title: Neurol Res. 30(7) Pages: 731-9
  • 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. 1219 Pages: 169-79
  • 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(8) Pages: 632-5
  • Peer Reviewed
• [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, George-Hyslop PS, Shoji M, Nakazato Y
  • Journal Title: Brain Res. 1214 Pages: 159-68
  • Peer Reviewed
• [Journal Article] Plasma biomarkers of Alzheimer's disease (2008)
  • Author(s): Kawarabayashi T, Shoji M
  • Journal Title: Curr Opin Psychiatry 21(3) Pages: 260-7
  • Peer Reviewed
• [Journal Article] The Japanese Genetic Study Consortium for Alzheimer's Disease, Consortium Information : Members are listed in the acknowledgements. 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(23) Pages: 2854-2869
  • Peer Reviewed
• [Journal Article] Enhanced accumulation of phosphorylated alpha-synuclein in double transgenic mice expressing mutant beta-amyloid precursor protein 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, Hyslop PS, Harigaya Y, Kamiya T, Shoji M, Abe K
  • Journal Title: J Neurosci Res. 85(10) Pages: 2246-52
  • Peer Reviewed
• [Journal Article] PINK1, 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, Kurata T, Takehisa Y, Matsubara E, Ikeda M, Harigaya Y, Shoji M, Takahashi R, Abe K
  • Journal Title: J Neurol Neurosurg Psychiatry 78(6) Pages: 653-4
  • 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, Ohta Y, Hayashi T, Shoji M, Abe K
  • Journal Title: Neurol Res. 29(8) Pages: 767-71
  • 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(10) Pages: 1502-8
  • 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(1) Pages: 4-8
  • Peer Reviewed
• [Presentation] Recent advances of Alzheimer disease research : diagnosis and therapy (2009)
  • Author(s): Mikio Shoji
  • Organizer: The 2009 International Symposium on early detection and rehabilitation of dementia
  • Place of Presentation: Okayama
  • Year and Date: 20091211-20091212
• [Presentation] Immune response to Aβ40 and Aβ42 in normal controls and patients with Alzheimer's disease (2009)
  • Author(s): Mikio Shoji
  • Organizer: The 11the meeting of Hirosaki International Forum of Medical Science
  • Place of Presentation: Hirosaki
  • Year and Date: 20090327-20090328
• [Presentation] 認知症 : 診断と治療 (2009)
  • Author(s): 東海林幹夫
  • Organizer: 第19回日本臨床精神神経薬理学会, 第39回日本神経精神薬理学会
  • Place of Presentation: 京都, 国際会館
  • Year and Date: 2009-11-14
• [Presentation] 認知症の診断と治療 (2009)
  • Author(s): 東海林幹夫
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-20
• [Presentation] CSF Tau correlates with Brain Tau In Tau Transgenic Mice (2008)
  • Author(s): Takeshi Kawarabayashi, Yusuke Seino, Yasuhito Wakasaya, Mitsunori Watanabe, Tamaki Kimura, Chieko Suzuki, Masahiko Tomiyama, Etsuro Matsubara, Koichi Ishiguro, David Westaway, Peter St. George-Hyslop, Mikio Shoji
  • Organizer: ICAD2008
  • Place of Presentation: Chicago
  • Year and Date: 20080726-20080731
• [Presentation] Ass oligomer : An essential therapeutic target for Alzheimer's disease. Brain'07 and Brain PET'07 (2007)
  • Author(s): Mikio Shoji
  • Organizer: The 23rd International Synmpsium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-22
• [Book] アルツハイマー病. 神経疾患最新の治療 (2009)
  • Author(s): 東海林幹夫
  • Total Pages: 179-186
  • Publisher: 南江堂
• [Book] 認知症の検査, 評価尺度, 認知症テキストブック (2008)
  • Author(s): 東海林幹夫
  • Total Pages: 234-251
  • Publisher: 中外医学社
• [Book] アルツハイマー病の診断 (2008)
  • Author(s): 東海林幹夫
  • Total Pages: 213-219
  • Publisher: 日本臨床社
• [Patent(Industrial Property Rights)] アルツハイマー病の検査法, アルツハイマー病に対して治療効果を有する物質のスクリーニング方法およびアルツハイマー病の検査キット (2010)
  • Inventor(s): 東海林幹夫, 渡辺光法
  • Industrial Property Rights Holder: 弘前大学, 北海道大学
  • Industrial Property Number: 特許特願2010-48003
  • Filing Date: 2010-03-04
• [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): 東海林幹夫, 瓦林毅
  • Industrial Property Rights Holder: 弘前大学, 京都大学, 北興化学
  • Industrial Property Number: 特許発開示08-21, 特願2008-301006
  • 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: 東海林幹夫, 池田将樹, 山田秀一
  • Industrial Property Number: 特許特許第4174212号
  • Filing Date: 2008-08-22