加齢に伴う翻訳後異常修飾蛋白蓄積の相互作用に関する臨床・実験神経病理学的研究

• Project/Area Number: 17390257
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Metropolitan Institute of Gerontology
• Principal Investigator: 村山 繁雄 Tokyo Metropolitan Institute of Gerontology, 東京都老人総合研究所, 研究部長 (50183653)
• Co-Investigator(Kenkyū-buntansha): 齊藤 祐子 (斉藤 祐子) 財)東京都高齢者研究・福祉振興財団, 東京都老人総合研究所, 研究員 (60344066)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,080,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥1,080,000); Fiscal Year 2007: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2006: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥7,800,000 (Direct Cost: ¥7,800,000)
• Keywords: 老人班 / 神経原線維変化 / 嗜銀顆粒 / レビー小体 / タウ / アルファシヌクレイン / アミロイドベータ蛋白 / ユビキチン / 老人斑 / アミロイドアンギオパチー / αシヌクレイン / アミロイドβ蛋白 / パーキンソン病 / アルツハイマー病 / レヴィー小体 / 老化 / 認知症 / スプライシング

Research Abstract

高齢者の変性型老化性変化の重複沈着の機構を明らかにする目的で、東京都老人医療センター連続開頭剖検例から文書同意を得た、高齢者ブレインバンク(BBAR)登録例に網羅的に、H.E.、KB.染色を通常とし、Gallyas-Braak・Methenamine鍍銀染色に、抗アミロイドβ蛋白(Aβ)(11-24)、リン酸化タウ(AT8)、リン酸化αシヌクレイン(psyn#64)、ユビキチン抗体で免疫染色を行う、BBARプロトコール(www.mci.gr.jp/BrainBank/)に基づき検討した。DNAが保存された1,628例中、老人班(SP)ステージ0-C、神経原線維変化(NFT)ステージI-VIに分類したところ、分散傾向が見られたが、NFT新皮質ステージには、Braak Stage Cが6例の例外を除き要求されることで、アミロイド仮説は新皮質では成立することが明らかとなった。一方、レビー小体型認知症(DLB)コンセンサスガイドライン(1996)に従ったレビースコアと、認知症・パーキンソン症状の有無で分類した、BBARステージ分類I-Vで同一集団を解析したところ、レビースコア新皮質ステージとSPステージCが相関することが明らかとなった。我々が提唱している嗜銀顆粒ステージ分類では、SP、NFTとも相関はみられなかった。一方、末梢自律神経系へのレビー小体病理の進展には、SP Stage C、NFT Stage IV以上が有意の負の相関をとることが明らかとなった。さらに、嗅球のレビー小体病理には、NFT Stageが有意ではないが正の影響を当てることが明らかとなった。以上の点より、新皮質では、タウ、シヌクレインの沈着はAβに影響を受け、辺縁系ではタウとシヌクレインが相互に影響し合い、シヌクレインの末梢への沈着は、アルツハイマー変化が抑制することが明らかとなった。

Research Products

• [Journal Article] Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lesy body disease. (2007)
  • Author(s): Fumimura Y, Ikemura M, Saito Y, Sengoku R, Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T, Fukayama M, Mizusawa H, Muravama S
  • Journal Title: J Neuropath Exp Neurol 66 Pages: 469-480
  • Peer Reviewed
• [Journal Article] Neuropathology of mild cognitive impairment. (2007)
  • Author(s): Saito Y, Murayama S
  • Journal Title: Neuropathology 104 Pages: 1387-1393
  • NAID: 10021237082
  • Peer Reviewed
• [Journal Article] Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lesy body disease. (2007)
  • Author(s): Fumimura, Y., Ikemura, M., ^*Saitom, Y., Sengoku, R., Kanemaru, K., Sawabe, M., Arai, T., Ito, G., Iwatsubo, T., Fukayama, M., Mizusawa, H., ^*Muravama, S
  • Journal Title: J Neuropath Exp Neurol 104・5 Pages: 469-480
  • Peer Reviewed
• [Journal Article] Lipocalin-type prostaglandin D synthase/β-trace is a major amyloid β-chaperone in human cerebrospinal fluid. (2007)
  • Author(s): Kanekiyo, T., Ban, T., Aritake, K., Huang, Z-L., Qu, W-M., Okazaki, I., Mohri, I., Murayama, S., Ozono, K., Taniike, M., Goto, Y., &^*Urade, Y.
  • Journal Title: PNAS 27・ Pages: 6412-6417
  • Peer Reviewed
• [Journal Article] Neuropathology of mild cognitive impairment. (2007)
  • Author(s): ^*Saito, Y.,& Murayama, S
  • Journal Title: Neuropathology 27 Pages: 578-584
  • NAID: 10021237082
  • Peer Reviewed
• [Journal Article] Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia. (2007)
  • Author(s): ^*Ishida K., Mitoma H., Wada Y., Oka T., Shibahara J. Saito Y., Muravama S., Mizusawa H.
  • Journal Title: J Neurol Neurosurg Psychiatry 78 Pages: 190-192
  • Peer Reviewed
• [Journal Article] Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration:consensus of the Consortium for Frontotemporal Lobar Degeneration. (2007)
  • Author(s): ^*Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL 3rd, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Muravama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM
  • Journal Title: Acta Neuropathol(Berl) 114 Pages: 5-22
  • Peer Reviewed
• [Journal Article] Prostaglandin D_2 receptor, DP_1 is selectively up-regulated in microglia and astrocytes within senile plaques from human patients and a mouse model of Alzheimer's disease. (2007)
  • Author(s): Mohri I, Kadoyama K, Kanekiyo T, Sato Y, Kagitani-Shimono K, Saito Y, Suzuki K, Kudo T, Takeda M, Urade Y, Murayama S, *Taniike M
  • Journal Title: J Neuropath Exp Neurol 66 Pages: 469-480
  • Peer Reviewed
• [Journal Article] Pathology of the sympathetic nervous system corresponding to the decreased cardiac uptake in 123I-metaiodobenzylguanidine (MIBG) scintigraphy in a patient with Parkinson disease. (2006)
  • Author(s): Mitsui J, Saito Y, Momose T, Shimizu J, Arai N, Shibahara J, Ugawa Y, Kanazawa I, Tsuji S, Murayama S
  • Journal Title: J Neurol Sci 243 Pages: 101-104
• [Journal Article] Multiple candidate gene analysis identifies a-synuclein as a susceptibility gene for sporadic Parkinson's disease. (2006)
  • Author(s): Mizuta I, Satake W, Nakabayashi Y, Ito C, Suzuki S, Momose Y, Nagai Y, Oka A, Inoko H, Fukae J, Saito Y, Sawabe M, Murayama S, Yamamoto M, Hattori N, Murata M, Toda T
  • Journal Title: Hum Mol Gen 15 Pages: 1151-8
• [Journal Article] Beta-site APP cleaving enzyme 1 (BACE1) is increased in remaining neurons in Alzheimer's disease brains. (2006)
  • Author(s): Harada H, Tamaoka A, Ishii K, Shoji S, Kametaka S, Kametani F, Saito Y, Murayama S:
  • Journal Title: Neurosci Res 54 Pages: 24-29
  • NAID: 10020614044
• [Journal Article] Increased levels of granular tau oligomers : an early sign of brain aging and Alzheimer's disease. (2006)
  • Author(s): Maeda S, Sahara N, Saito Y, Murayama S, Ikai A, Takashima A
  • Journal Title: Neurosci Res 54 Pages: 179-201
  • NAID: 10017323753
• [Journal Article] Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients. (2006)
  • Author(s): Umemura K, Yamashita N, Yu X, Arima K, Asada T, Makifuchi T, Murayama S, Saito Y, Kanamaru K, Goto Y, Kohsaka S, Kanazawa I, Kimura H
  • Journal Title: Neurosci Lett 400 Pages: 97-100
• [Journal Article] Sustained progression and loss of the gender-related difference in atherosclerosis in the very old : A pathological study of 1074 consecutive autopsy cases. (2006)
  • Author(s): Sawabe M, Arai T, Kasahara I, Hamamatsu A, Esaki Y, Nakahara K, Harada K, Chiba K, Yamanouchi H, Ozawa T, Takubo K, Murayama S, Tanaka N
  • Journal Title: Atherosclerosis 186 Pages: 374-379
• [Journal Article] An immunohistochemical study of cases of sporadic and inherited forntotemproal lobar degeneration using 3R-and 4R-spefici tau monoclonal antibodies. (2006)
  • Author(s): Silva R, Lashely T, Strand C, Shiarli AM, Shi J, Tian J, Bailery, KL, Davies P, Higo EH, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Halliday G, Mackenzie J, Ravid R, Dicskon D, Wszolek Z, Iwatsubo T, Pickering-Brosn SM, Hoton J, Lees A, Tavesz T, Mann DMA
  • Journal Title: Acat Neuropathologica 111 Pages: 329-340
• [Journal Article] Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease. (2006)
  • Author(s): Shiarli AM, Jennings R, Shi J, Bailey K, Davidson Y, Tian J, Bigio EH, Ghetti B, Murrell JR, Delisle MB, Mirra S, Crain B, Zolo P, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Haliday G, Mackenzie J, Khan N, Ravid R, Dickson D, Wazolek Z, Iwatsubo T, Pickering-Brown SM, Mann DM
  • Journal Title: Neuropathol Appl Neurobiol 32 Pages: 374-387
• [Journal Article] Unique tauopathy in Fukuyama-type congenital muscular dystrophy. (2005)
  • Author(s): Saito Y, Motoyoshi Y, Kashima T, Izumiyama-Shimomura N, Toda T, Nakano I, Hasegawa M, Murayama S
  • Journal Title: J Neuropath Exp Neurol 64 Pages: 1118-1126
  • Peer Reviewed
• [Journal Article] Idependent accumulations of tau and amyloid β-protein in the human entorhinal cortex. (2005)
  • Author(s): Katsuno T, Morishima-Kawashima M, Saito Y, Yamanouchi H, Ishiura S, Murayama S, Ihara Y
  • Journal Title: Neurology 64 Pages: 687-692
• [Journal Article] Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease. (2005)
  • Author(s): Ishigami A, Ohsawa T, Hiratsuka M, Taguchi H, Kobayashi S, Saito Y, Murayama S, Asaga H, Toda T, Kimura N, Maruyama N
  • Journal Title: Neurosci Res 80 Pages: 120-128
• [Journal Article] Possibility for neurogenesis in the substantia nigra of Parkinsonian brain. (2005)
  • Author(s): Yoshimi K, Ren Yong-Ri, Seki T, Yamada M, Ooizumi H, Onodera M, Saito Y, Murayama S, Okano H, Mizuno Y, Mochizuki H
  • Journal Title: Ann Neurol 58 Pages: 31-40
• [Journal Article] Possibility for neurogenesis in the substantia nigra of Parkinsonian brain. (2005)
  • Author(s): Saito Y, Motoyoshi Y, Kashima T, Izumiyama-Shimomura N, Toda T, Nakano I, Hasegawa M, Murayama S
  • Journal Title: Ann Neurol 58 Pages: 31-40
• [Presentation] Characterization of therapeutic antibody against Aβ oligomcrs for Alzheimer's disease. (2007)
  • Author(s): Sun, H., Okamoto Y., Kawarabayashi, Kawarabayashi, T., Yokoseki, T., M. Shibata, M., Morishima,, Saito, Y., Murayama, S., Ihara, Y., Shoji, M., Hoji, M., Michikawa, M., *Matsubara, E
  • Organizer: 2007Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2007-11-05
• [Presentation] TDP 43 immunocytochemistry is sentisitve but not specific method to detect motor neuron-disease type neuronal inclusions. (2007)
  • Author(s): *Murayama S, Saito Y, Hatsuta H:
  • Organizer: 83rd Annual Meeting of the Amerian Association for Neuropathologists
  • Place of Presentation: Wahington D.C.
• [Presentation] The Brain Bank for Aging Research,Japan. (2007)
  • Author(s): *Murayama S, Saito Y, Kanamaru K, Ishii K, Tokumaru A
  • Organizer: 2007World Congress of International Brain Research Organization
  • Place of Presentation: Melbourne
• [Presentation] The Brain Bank for Aging Research Project, Japan. (2007)
  • Author(s): *Murayama S, Saito Y, Kanamaru K, Ishii K, Tokumaru A
  • Organizer: Intenational Geriatric Psychiatry
  • Place of Presentation: Osaka
• [Presentation] Adrenal gland is useful to evaluate peripheral autonomic nervous system in Lewy body disease. (2007)
  • Author(s): *Murayama S, Saito Y, Ikemura M
  • Organizer: 5th Congress of the International Society for Autonomic Neuroscience
  • Place of Presentation: Kyoto
• [Presentation] Synergetic effect of Alzheimer and Parkinson changes on dementia. (2005)
  • Author(s): Saito Y, Kanemaru K, Arai T, Sawabe M, Murayama S
  • Organizer: World Congress of Neurology
  • Place of Presentation: Sydney
• [Book] Annual Review神経病理2007、中外医学社、東京 (2007)
  • Author(s): 村山 繁雄, 齊藤 祐子
  • Publisher: PDD(認知症を伴うパーキンソン病)とDLB(レヴィー小体型認知症)の臨床と病理。
• [Book] アルツハイマー病診断 (2006)
  • Author(s): 村山繁雄 編著
  • Total Pages: 234
  • Publisher: 真興交易 (株)医書出版部