Molecular mechanism underlying Ass assembly in Alzheimer brain : pathological and therapeutic significance of an endogenous seed for amyloid

2009 Fiscal Year Final Research Report

• Project/Area Number: 17025057
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Institute for Longevity Sciences,NCGG
• Principal Investigator: YANAGISAWA Katsuhiko National Institute for Longevity Sciences,NCGG, 副所長 (10230260)
• Project Period (FY): 2005 – 2009
• Keywords: アルツハイマー病 / アミロイド蛋白 / ガングリオシド / アポリポ蛋白 / シナプス / マイクロドメイン / 遺伝的変異型

Research Abstract

アルツハイマー病のアミロイドss蛋白質(Ass)の重合には神経細胞膜の糖脂質であるガングリオシドに結合したAss(GAss)がアミロイドの"種"として働いていると考えられる。本研究では、GAssの形成に神経細胞内の膜輸送の障害が関わり、ガングリオシドが密集した特異な膜ドメインが形成されることが必要であることを確認した。またGAssの"種"作用の抑制により脳内におけるアミロイド形成を阻害する新しい治療法の開発を検討した。

Research Products

• [Journal Article] Surface-induced phase separation of a sphingomyelin / cholesterol / ganglioside GM1-planar bilayer on mica surfaces and microdomain molecular conformation that accelerates As oligomerization (2010)
  • Author(s): Mao Y, Zhiguo S, Imai Y, Hoshino T, Tero R, Tanaka M, Yamamoto N, Yanagisawa K, Urisu T.
  • Journal Title: Biochim Biophys Acta (in press) Pages: 22-26
  • Peer Reviewed
• [Journal Article] Gender effect on the accumulation of hyperphosphorylated tau in the brains of locus-ceruleus-injured APP transgenic mouse (2010)
  • Author(s): Oikawa N, Ogino K, Masumoto T, Yamaguchi H, Yanagisawa K.
  • Journal Title: Neurosci. Lett. 468 Pages: 243-247
  • Peer Reviewed
• [Journal Article] Alzheimer-type tau pathology in advanced nonhuman primate brains harboring substantial amyloid depositio (2010)
  • Author(s): Oikawa N, Kimura N, Yanagisawa K.
  • Journal Title: Brain. Res. 1315 Pages: 137-149
  • Peer Reviewed
• [Journal Article] Up-and-down topological mode of amyloid s-peptide lying on hydrophilic / hydrophobic interface of ganglioside clusters (2009)
  • Author(s): Utsumi M, Yamaguchi Y, Sasakawa H, Yamamoto N, Yanagisawa K, Kato K.
  • Journal Title: Glycoconjugate J. 26 Pages: 999-1006
  • Peer Reviewed
• [Journal Article] Gangliosides determine the amyloid pathology of Alzheimer disease (2009)
  • Author(s): Oikawa N, Yamaguchi H, Ogino K, Taki T, Yuyama K, Yamamoto N, Shin R-W., Furukawa K, Yanagisawa K.
  • Journal Title: Neuroreport 20 Pages: 143-1046
  • Peer Reviewed
• [Journal Article] ate endocytic dysfunction as a putative cause of amyloid fibril formation in Alzheimer's disease (2009)
  • Author(s): Yuyama K, Yanagisawa K.
  • Journal Title: J. Neurochem 109 Pages: 1250-1260
  • Peer Reviewed
• [Journal Article] ate endocytic dysfunction as a putative cause of amyloid fibril formation in Alzheimer's disease (2009)
  • Author(s): Yuyama., Yanagisawa K.
  • Journal Title: J. Neurochem 109 Pages: 1250-1260
  • Peer Reviewed
• [Journal Article] ccelerated release of exosome-associated GM1 ganglioside (GM1) by endocytic pathway abnormality: another putative pathway for GM1-induced amyloid fibril formation (2008)
  • Author(s): Yuyama K, Yamamoto N, Yanagisawa K.
  • Journal Title: J. Neurochem 105 Pages: 217-224
  • Peer Reviewed
• [Journal Article] Age-dependent high-density clustering of GM1 ganglioside at presynaptic neuritic terminals promotes amyloid s-protein fibrillogenesis (2008)
  • Author(s): Yamamoto N, Matusbara T, Sato T. Yanagisawa K.
  • Journal Title: Biochim. Biophys. Acta 1778 Pages: 2717-2726
  • Peer Reviewed
• [Journal Article] A ganglioside -induced toxic soluble As assembly: Its enhanced formation from As bearing theArctic mutation (2007)
  • Author(s): amamoto N, Matsubara E, Maeda S, Minagawa H, Takashima A, Maruyama W, Michikawa M, Yanagisawa, K.
  • Journal Title: J. Biol. Chem 282 Pages: 2646-2656
  • Peer Reviewed
• [Journal Article] GM1-ganglioside-induced As assembly on synaptic membranes of cultured neurons (2007)
  • Author(s): Yamamoto N, Fukata Y, Fukata M, Yanagisawa K.
  • Journal Title: Biochim. Biophys. Acta 1768 Pages: 1128-1137
  • Peer Reviewed
• [Journal Article] Chloroquine-induced endocytic pathway abnormalities: cellular model of GM1 -ganglioside-induced As fibrillogenesis in Alzheimer's disease (2006)
  • Author(s): Yuyama K, Yamamoto N, Yanagisawa K.
  • Journal Title: FEBS Lett 580 Pages: 6972-6976
  • Peer Reviewed
• [Journal Article] Assembly of hereditary amyloid s-protein variants in the presence of favorable gangliosides (2005)
  • Author(s): Yamamoto N, Hirabayashi Y, Amari M, Yamaguchi H, Romanov G, Van Nostr, W.E., Yanagisawa K.
  • Journal Title: FEBS Lett 579 Pages: 2185-2190
  • Peer Reviewed
• [Journal Article] Cross seeding of wild- and hereditary variant-type amyloid s-proteins in the presence of gangliosides (2005)
  • Author(s): Yamamoto N, Matsuzaki K, Yanagisawa K.
  • Journal Title: J. Neurochem. 95 Pages: 1167-1176
  • Peer Reviewed
• [Journal Article] Suppression of As deposition in brain by peripheral administration of Fab fragments of anti-seed antibody (2005)
  • Author(s): Yamamoto N, Yokoseki T, Shibata M, Yamaguchi H, Yanagisawa K.
  • Journal Title: Biochem. Biophys. Res. Commun. 335 Pages: 45-47
  • Peer Reviewed
• [Presentation] Lipid metabolism and its pathophysiology in CNS (2009)
  • Author(s): シンポジウム
  • Organizer: 第51回日本脂質生化学会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-07-30
• [Presentation] アルツハイマー病におけるGM1ガングリオシド誘導性アミロイドs蛋白質重合に関与する後期エンドサイトーシス障害 (2009)
  • Author(s): 湯山耕平, 柳澤勝彦
  • Organizer: 第52回日本神経化学会大会
  • Place of Presentation: 渋川
  • Year and Date: 2009-06-22
• [Presentation] カニクイザル脳におけるアルツハイマー病関連蛋白(As、タウ)の解析 (2008)
  • Author(s): 及川尚人, 木村展之, 柳澤勝彦
  • Organizer: 第27回日本認知症学会
  • Place of Presentation: 前橋
  • Year and Date: 2008-10-11
• [Presentation] As線維化に関与するGM1ガングリオシド集積を誘導するエンドサイトーシス経路障害 (2008)
  • Author(s): 湯山耕平, 山本直樹, 柳澤勝彦
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-21
• [Presentation] シナプス前膜の年齢依存的なGM1 ganglioisde集積ドメイン形成はAs線維化を促す (2008)
  • Author(s): 山本直樹, 松原輝彦, 湯山耕平, 佐藤智典, 柳澤勝彦
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-12
• [Presentation] A ganglioside-induced soluble As assembly causes neuronal death through NGF receptors (2007)
  • Author(s): Yamamoto N, Matsubara E, Maeda S, Minagawa H, Takashima A, Michikawa M, Yanagisawa K.
  • Organizer: 37th Society for Neuroscience Annual Meeting
  • Place of Presentation: サンディエゴ, アメリカ
  • Year and Date: 2007-11-05
• [Presentation] エンドサイトーシス経路異常によるGM1ガングリオシドの細胞外放出の促進 (2007)
  • Author(s): 湯山耕平, 山本直樹, 柳澤勝彦
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-10
• [Presentation] 老齢マウス脳シナプス膜中の特異なGM1 ganglioside集積ドメイン (2007)
  • Author(s): 山本直樹, 湯山耕平, 柳澤勝彦
  • Organizer: 50回日本神経化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-10
• [Presentation] A ganglioside-induced toxic soluble As assemblycauses neuronal death (2006)
  • Author(s): 山本直樹, 松原悦朗, 前田純裕, 高島明彦, 丸山和佳子, 道川誠, 柳澤勝彦
  • Organizer: 第29回日本分子生物学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2006-12-06
• [Presentation] GM1-ganglioside-induced As assembly at neuritic terminals of nerve growth factor-treated PC12 cells (2006)
  • Author(s): 山本直樹, 湯山耕平, 柳澤勝彦
  • Organizer: 第49回日本神経化学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2006-09-14
• [Presentation] GM1 ganglioside accumulation in PC12 cells treated with chloroquine: a cellular model of As assembly (2006)
  • Author(s): 湯山耕平, 山本直樹, 柳澤勝彦
  • Organizer: 第49回日本神経化学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2006-09-14
• [Presentation] Pivotal roles of lipids in generating an endogenous seed for Alzheimer amyloid (2005)
  • Author(s): Yanagisawa K.
  • Organizer: 7th International Conference on Alzheimer's Disease and Parkinson Disease. Sorrento
  • Place of Presentation: イタリア
  • Year and Date: 20050509-20050514
• [Presentation] 膜マイクロドメインとアルツハイマー病:GM1ガングリオシド集積の意味 (2005)
  • Author(s): 柳澤勝彦
  • Organizer: 第28回日本分子生物学会
  • Place of Presentation: 福岡
  • Year and Date: 2005-12-10
• [Presentation] Assembly of hereditary variant amyloid s-protein in the presence of gangliosides (2005)
  • Author(s): Yamamoto N, Hirabayashi Y, Amari M, Yamaguchi H, Romanov G, Nostr, W, Yanagisawa K.
  • Organizer: 第48回日本神経化学会
  • Place of Presentation: 福岡
  • Year and Date: 2005-09-28
• [Presentation] アミロイドs蛋白重合とガングリオシド (2005)
  • Author(s): 柳澤勝彦
  • Organizer: 第28回日本神経科学大会シンポジウム「糖鎖科学と神経科学の融合による新展開」
  • Place of Presentation: 横浜
  • Year and Date: 2005-07-27
• [Presentation] Pathological significance of ganglioside cluster in Alzheimer disesse
  • Author(s): 柳澤勝彦
• [Book] Research Progress in Alzheimer's Disease(edited by Miao-Kun Sun, Pivotal roles of cholesterol and gangliosides in aggregation of amyloid β-protein.) (2010)
  • Author(s): Yanagisawa K.
  • Publisher: Nova Science Pulishers, Inc.(in press)
• [Book] Comprehensive Glycoscience(edited by Kamerling J.P., Boons G-J., Lee Y.C.,Suzuki A. and Taniguchi N., Glycoconjugates and neurological diseases.) (2007)
  • Author(s): Yanagisawa K, Yuki N.
  • Total Pages: 495-513
  • Publisher: Elsevier
• [Book] Sphingolipid Biology.(edited by Hirabayashi Y, Igarashi Y and Merill AH, Ganglioside and Alzheimer's disease.) (2006)
  • Author(s): Yanagisawa K.
  • Total Pages: 309-317
  • Publisher: Springer
• [Book] Recent Progress in Alzheimer's and Parkinsons's Diseases(edited by Hanin I,Casabelos R and Fisher A, Cholesterol and Aβ cascade:pathological implication of apolipoprotein E in Alzheimer's disease.) (2005)
  • Author(s): Yanagisawa K.
  • Total Pages: 133-137
  • Publisher: Taylor & Francis
• [Book] Cholesterol and amyloid β fibrillogenesisIn: Alzheimer's Disease: Cellular and Molecular Aspects of Amyloid β(edited by Robin Harris and Falk Fahrenholz) (2005)
  • Author(s): Yanagisawa, K.
  • Total Pages: 179-202
  • Publisher: Springer-Verlag
• [Patent(Industrial Property Rights)] 可溶性アミロイドs蛋白重合体の調整法ならびに毒性評価法 (2006)
  • Inventor(s): 柳澤勝彦、山本直樹
  • Industrial Property Rights Holder: ヒューマンサイエンス振興財団
  • Industrial Property Number: 特許権
  • Filing Date: 2006-06-05