2000 Fiscal Year Annual Research Report

脳老化を制御するプロテアーゼシステムの解明

Research Project

Project/Area Number	12210019
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	The Institute of Physical and Chemical Research
Principal Investigator	西道隆臣理化学研究所, 神経蛋白制御研究チーム, チームリーダー(研究職) (80205690)
Keywords	アルツハイマー病 / βアミロイド / 中性エンドペプチダーゼ / ネプリライシン / カルパイン / カスパーゼ / プロテアソーム / カルパスタチン
Research Abstract	(1)βアミロイド分解システムの同定と制御動物脳内におけるβアミロイドペプチド(Aβ)の分解系路を明らかにするためにラジオアイソトープで多重標識したAβを投与する実験システムを用い、以下の点を明らかにした。[1]βアミロイドペプチドは脳実質内のプロテアーゼによって分解される。[2]分解における主要な中間体はAβ10-37であり、この中間体の生成が律速過程を担う。[3]この中間体を生成するプロテアーゼは、ネプリライシン様の中性メタロエンドペプチダーゼである。[4]動物脳において分解システムを抑制することによってβアミロイドの蓄積が促進される。さらに、分解酵素について分子生物学的・生化学的・発生工学的検討を行い、ネプリライシンが脳内における主要なAβ分解酵素であることを示した。 (2)神経細胞質内プロテアーゼ群の病理作用の解析脳老化制御における主要な細胞内プロテアーゼ群であるカスパーゼ・カルパイン・プロテアソームの役割を解析するために、カスパーゼインヒビター(p35)・カルパインインヒビター(カルパスタチン)・プロテアソームユビキチンリセプターサブユニット(S5a)を神経細胞に発現するトランスジェニックマウスの作成を開始した。p35トランスジェニックマウスについてはライン化に成功し、現在解析を進めている。他のマウスについても複数のラインが得られつつある。

Research Products

(28 results)

All Other

All Publications (28 results)

[Publications] Iwata,N.,Tsubuki,S.,Takaki,Y.,Watanabge,K.,Sekiguchi,M.,Hosoki,E.,Kawashima-Morishima,M.,Lee,H.-J.,Hama,E.,Sekine-Aizawa,Y.,Saido,T,C.: "Identification of the major Aβ1-42-degrading catabolic pathway in brain parenchyma : Suppression leads to biochemical and pathological deposition."Nature Med.. 6. 143-151 (2000)
[Publications] Shimokata,H.,Yamada,Y.,Nakagawa,M.,Okubo,R.,Saido,T.C.,Funakoshi,A.,Miyasaka,K.,Ohota,S.,Tsujimoto,G., Tanaka,M.,Ando,F.,Niino,N.: "Distribution of geriatric disease-related genotypes in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA)."J.Epiderm. S46-55. (2000)
[Publications] Russo,C.,Schettini,G.,Saido,T.C.,Hulette,C.,Lippa,C.,Lannfelt,L.,Ghetti,B.,Gambetti,P.,Tabaton,M.,Teller,J.K.: "Preferential deposition of truncated amyloid-βpentides in brain of presenilin 1 gene mutation carriers."Nature. 405. 531-532 (2000)
[Publications] Nakagawa,Y.,Reed,L.,Nakamura,M.,McIntosh,T.K.,Smith,D.H.,Saatman,K.E.,Raghupathi,R.,Clemens,J.,Saido,T.C.,Lee,Virginia M.E.,Troianowski, I.Q.: "Brain trauma in aged transgenic mice induces regression of established Aβdeposit."Exper.Neurol.. 163. 244-252. (2000)
[Publications] Lankiewicz,S.,Luetjens,C.M.,Bui,N.T.,Krohn,A..J.,Poppe,M.,Cole,G.C.,Nicholson,D.W.,Saido,T.C.,Prehn,H.M.: "Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death."J.Biol.Chem.. 275. 17064-17071 (2000)
[Publications] Takeuchi,A.,Irizarry,M.C.,Duff,K.,Saido,T.C.,Hsiao,Ashe K.,Hasegawa,M.,Mann D.M.A.,Hyman,B.T.,Iwatsubo,T.: "Age-related Aβdeposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and βamyloid precursor protein is not associated with global neuronal loss."Am.J.Pathol.. 157. 331-339 (2000)
[Publications] Hiwasa,T.,Arase,Y.,Kikuno,K.,Hasegawa,R.,Sugaya,S.,Kita,K.,Saido,T.,Yamamori,H.,Maki,M.,Suzuki,N.: "Increase in ultraviolet sensitivity by overexpression of calpastatin in ultraviolet-resistant UVr-1 cells derived from ultraviolet-sensitive human RSa cells."Cell death and Differentiation. 7. 531-537 (2000)
[Publications] Iwata,N.,Tsubuki,S.,Hama,E.,Takaki,Y.,Shirotani, K.,Saido,T.C.: "Clearance of amyloid β-peptide from brain : transport or metabolism?"Nature Med.. 6. 718-719 (2000)
[Publications] Harigaya,Y.,Saido,T.C.,Eckman,C.B.,Prada,C.-M.,Shoji,M.,Younkin,S.: "Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain."Biochem.Biophys.Res.Commun.. 276. 422-427 (2000)
[Publications] Saido,T.C.: "Degradation of amyloid-βpeptide : a key to Alzheimer pathogeneis, prevention, and therapy."NeuroSci.News. 5(3). 52-62 (2000)
[Publications] Lee,H.-J.,Tomioka,M.,Takaki,Y.,Masumoto,H.,Saido,T.C.: "Molecular cloning and expression of aminopeptiase A isoforms from rat hippocampus."Biochim.Biophys.Acta. 1493. 273-278 (2000)
[Publications] Takaki,Y.,Iwata,N.,Tsubuki,S.,Taniguchi,S.,Toyoshima,S.,Lu,B.,Gerard,N.P.,Gerard,C.,Lee,H.-J.,Shirotani,K.,Saido,T.C.: "Biochemical Identification of the neutral endopeptidase family member responsible for the catabolism of amyloid βpeptide in brain."J.Biochem. 128. 897-902 (2000)
[Publications] Koike,H.,Kouchi,Z.,Kinouchi,T.,Maeda,T.,Sorimachi,H.,Saido,T.C.,Maruyama,K.,Okuyama,A.,Suzuki,K.,Ishiura,S.,.: "Metabolism of amyloid precursor protein in COS cells transfected with a beta-secretase candidate.Cytotechnol."J.Biol.Chem.. 33. 213-219 (2000)
[Publications] Kitagaki,H.,Tomioka,S.,Yoshizawa,T.,Sorimachi,H.,Saido,T.C.,Ishiura,S.,Suzuki,K.: "Autolysis of calpain large subunit inducing irreversible dissociation of stoichiometric heterodimer of calpain."Biosci.Biotechnol.Biochem.. 64. 689-695 (2000)
[Publications] Shoji,M.,Kawarabayashi,T.,Sato,M.,Sasaki,A.,Saido,T.C.,Matsubara,E.,Yomidokoro,Y.,Kanai,M.,Shizuka,M.,Ishiguro,K.,Ikeda,M.,Harigaya,Y.,Okamoto,K.,Hirai,S.: "Age-related amyloid beta protein accumulation induces cellular death and macrophage activation in transgenic mice."J.Pathol.. 191. 93-101 (2000)
[Publications] Yamaguchi,A.,Yamamoto,N.,Akamatsu,N.,Saido,T.C.,Kaneda,M.,Umeda,M.,Tanoue,K.: "PS-liposome and ox-LDL bind to different sites of the immunodominant domain (#155-183) of CD 36 : a new study with GS95, a new anti-CD36 monoclonal antibody."Thromb.Res.. 97. 317-326 (2000)
[Publications] Maruyama,K.,Usami,M.,Kametani,F.,Tomita,T.,Iwatsubo,T.,Saido,T.C.,Mori,H.,Ishiura,S.: "Molecular interactions between presenilin and calpain : inhibition of m-calpain protease activity by presenilin-1,2 and cleavage of presenilin-1 by m-,mu-calpain,Int."J.Mol.Med.. 5. 269-273 (2000)
[Publications] Bialkowska,K.,Kulkarni,S.,Du,X.,Goll,D.E.,Saido,T.C.,Fox,J.E.B.: "Evidence that beta3 integrin-induced Rac activation involves the calpain-dependent formation of integrin clusters that are distinct from the focal complexes and focal adhesions that form as Rac and RhoA become active."J.Cell Biol.. 151. 685-695 (2000)
[Publications] Kawarabayashi,T.,Younkin,L.H.,Saido,T.C.,Shoji,M.,K.Hsiao,A.,Younkin,S.G.,.: "Age-dependent changes in brain, cerebrospinal fluid, and plasma amyloid βprotein in the Tg2576 transgenic mouse model of Alzheimer's disease."J.Neurosci.. 21. 372-381 (2001)
[Publications] Taniguchi,S.,Fujita,Y.,Takahashi,H.,Hayashi,S.,Kakita,A.,Murayama,S.,Saido,T.C.,Hisanaga,S.,Iwatsubo,T.,Hasegawa,M.: "Degradation of p35 to p25 in postmortem human and rat brains."FEBS Lett. (in press). (2001)
[Publications] Sekine-Aizawa,Y.,Hama,E.,Watanabe,K.,Tsubuki,S.,Kanai-Azuma,M.,Kanai,Y.,Arai,H.,Aizawa,H.,Iwata,N.,Saido,T.C.: "Matrix metalloproteinase (MMP) system in brain : Identification and characterization of brain-specific MMP highly expressed in cerebellum"Eur.J.Neurosci.. (in press). (2001)
[Publications] 城谷圭朗,西道隆臣: "アミロイド沈着抑制とγ-セクレターゼ阻害剤"Pharma Medica. 18(2). 109-113 (2000)
[Publications] 高木淑江,岩田修永,西道隆臣: "Aβ産出・代謝・蓄積のメカニズム"脳の科学. 増刊. 111-116 (2000)
[Publications] 岩田修永,西道隆臣: "βアミロイドの脳内分解"Dementia Japan. 14. 80-88 (2000)
[Publications] 津吹聡,岩田修永,西道隆臣: "Aβ分解系に関する新知見"最新医学. 55. 31-37 (2000)
[Publications] 濱江美,西道隆臣: "アルツハイマー病の発症を抑える酵素"遺伝. 54. 9-10 (2000)
[Publications] 益本創,西道隆臣: "アルツハイマー病治療の分子標的"化学と生物. 38. 566-567 (2000)
[Publications] 丸山敬,西道隆臣: "人はなぜ痴呆になるのかアルツハイマー病の謎をさぐる"丸善ライブラリー. 199 (2000)

2000 Fiscal Year Annual Research Report

脳老化を制御するプロテアーゼシステムの解明

Principal Investigator

西道 隆臣 理化学研究所, 神経蛋白制御研究チーム, チームリーダー(研究職) (80205690)

Research Products

[Publications] Russo,C.,Schettini,G.,Saido,T.C.,Hulette,C.,Lippa,C.,Lannfelt,L.,Ghetti,B.,Gambetti,P.,Tabaton,M.,Teller,J.K.: "Preferential deposition of truncated amyloid-βpentides in brain of presenilin 1 gene mutation carriers."Nature. 405. 531-532 (2000)

[Publications] Nakagawa,Y.,Reed,L.,Nakamura,M.,McIntosh,T.K.,Smith,D.H.,Saatman,K.E.,Raghupathi,R.,Clemens,J.,Saido,T.C.,Lee,Virginia M.E.,Troianowski, I.Q.: "Brain trauma in aged transgenic mice induces regression of established Aβdeposit."Exper.Neurol.. 163. 244-252. (2000)

[Publications] Lankiewicz,S.,Luetjens,C.M.,Bui,N.T.,Krohn,A..J.,Poppe,M.,Cole,G.C.,Nicholson,D.W.,Saido,T.C.,Prehn,H.M.: "Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death."J.Biol.Chem.. 275. 17064-17071 (2000)

[Publications] Iwata,N.,Tsubuki,S.,Hama,E.,Takaki,Y.,Shirotani, K.,Saido,T.C.: "Clearance of amyloid β-peptide from brain : transport or metabolism?"Nature Med.. 6. 718-719 (2000)

[Publications] Harigaya,Y.,Saido,T.C.,Eckman,C.B.,Prada,C.-M.,Shoji,M.,Younkin,S.: "Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain."Biochem.Biophys.Res.Commun.. 276. 422-427 (2000)

[Publications] Saido,T.C.: "Degradation of amyloid-βpeptide : a key to Alzheimer pathogeneis, prevention, and therapy."NeuroSci.News. 5(3). 52-62 (2000)

[Publications] Lee,H.-J.,Tomioka,M.,Takaki,Y.,Masumoto,H.,Saido,T.C.: "Molecular cloning and expression of aminopeptiase A isoforms from rat hippocampus."Biochim.Biophys.Acta. 1493. 273-278 (2000)

[Publications] Takaki,Y.,Iwata,N.,Tsubuki,S.,Taniguchi,S.,Toyoshima,S.,Lu,B.,Gerard,N.P.,Gerard,C.,Lee,H.-J.,Shirotani,K.,Saido,T.C.: "Biochemical Identification of the neutral endopeptidase family member responsible for the catabolism of amyloid βpeptide in brain."J.Biochem. 128. 897-902 (2000)

[Publications] Koike,H.,Kouchi,Z.,Kinouchi,T.,Maeda,T.,Sorimachi,H.,Saido,T.C.,Maruyama,K.,Okuyama,A.,Suzuki,K.,Ishiura,S.,.: "Metabolism of amyloid precursor protein in COS cells transfected with a beta-secretase candidate.Cytotechnol."J.Biol.Chem.. 33. 213-219 (2000)

[Publications] Kitagaki,H.,Tomioka,S.,Yoshizawa,T.,Sorimachi,H.,Saido,T.C.,Ishiura,S.,Suzuki,K.: "Autolysis of calpain large subunit inducing irreversible dissociation of stoichiometric heterodimer of calpain."Biosci.Biotechnol.Biochem.. 64. 689-695 (2000)

[Publications] Yamaguchi,A.,Yamamoto,N.,Akamatsu,N.,Saido,T.C.,Kaneda,M.,Umeda,M.,Tanoue,K.: "PS-liposome and ox-LDL bind to different sites of the immunodominant domain (#155-183) of CD 36 : a new study with GS95, a new anti-CD36 monoclonal antibody."Thromb.Res.. 97. 317-326 (2000)

[Publications] Maruyama,K.,Usami,M.,Kametani,F.,Tomita,T.,Iwatsubo,T.,Saido,T.C.,Mori,H.,Ishiura,S.: "Molecular interactions between presenilin and calpain : inhibition of m-calpain protease activity by presenilin-1,2 and cleavage of presenilin-1 by m-,mu-calpain,Int."J.Mol.Med.. 5. 269-273 (2000)

[Publications] Kawarabayashi,T.,Younkin,L.H.,Saido,T.C.,Shoji,M.,K.Hsiao,A.,Younkin,S.G.,.: "Age-dependent changes in brain, cerebrospinal fluid, and plasma amyloid βprotein in the Tg2576 transgenic mouse model of Alzheimer's disease."J.Neurosci.. 21. 372-381 (2001)

[Publications] Taniguchi,S.,Fujita,Y.,Takahashi,H.,Hayashi,S.,Kakita,A.,Murayama,S.,Saido,T.C.,Hisanaga,S.,Iwatsubo,T.,Hasegawa,M.: "Degradation of p35 to p25 in postmortem human and rat brains."FEBS Lett. (in press). (2001)

[Publications] 城谷圭朗,西道隆臣: "アミロイド沈着抑制とγ-セクレターゼ阻害剤"Pharma Medica. 18(2). 109-113 (2000)

[Publications] 高木淑江,岩田修永,西道隆臣: "Aβ産出・代謝・蓄積のメカニズム"脳の科学. 増刊. 111-116 (2000)

[Publications] 岩田修永,西道隆臣: "βアミロイドの脳内分解"Dementia Japan. 14. 80-88 (2000)

[Publications] 津吹聡,岩田修永,西道隆臣: "Aβ分解系に関する新知見"最新医学. 55. 31-37 (2000)

[Publications] 濱江美,西道隆臣: "アルツハイマー病の発症を抑える酵素"遺伝. 54. 9-10 (2000)

[Publications] 益本創,西道隆臣: "アルツハイマー病治療の分子標的"化学と生物. 38. 566-567 (2000)

[Publications] 丸山敬,西道隆臣: "人はなぜ痴呆になるのか アルツハイマー病の謎をさぐる"丸善ライブラリー. 199 (2000)

西道隆臣理化学研究所, 神経蛋白制御研究チーム, チームリーダー(研究職) (80205690)

[Publications] 丸山敬,西道隆臣: "人はなぜ痴呆になるのかアルツハイマー病の謎をさぐる"丸善ライブラリー. 199 (2000)