2005 Fiscal Year Final Research Report Summary
The identification and therapeutic intervention of acceleratinf agent for Aβ clearance out of the brain
| Project/Area Number |
16590829
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology (2005)
Okayama University (2004) |
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Principal Investigator |
MATSUBARA Etsuro National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Chief, (研究所)・アルツハイマー病研究部, 室長 (70219468)
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| Co-Investigator(Kenkyū-buntansha) |
SHOJI Mikio Hirosaki University, Professor, 医学部, 教授 (60171021)
ABE Koji Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯薬学総合研究科, 教授 (20212540)
IKEDA Masaki Gunma University, Graduate School of Medicine, Instructor, 大学院・医学系研究科, 助手 (50222899)
ORIUCHI Noboru Gunma Univeristy, Graduate School of Medicine, Associated professor, 大学院・医学系研究科, 助教授 (40292586)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Alzheimer's disease / Aβ oligomer / ELISA / melatonin / clearance |
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| Research Abstract |
To assess whether melatonin is accelerating agent for Aβ clearance out of the brain, we investigated it in transgenic model mice for Alzheimer's disease (AD). It is relevant to note that melatonin has ability to upregulate Aβ clearance out of the brain, by driving the equilibrium not only from insoluble to soluble, but also from oligomeric to monomeric Aβ. Melatonin also corrected the spatial reference memory performance without reducing senile plaques burdens in the APP transgenic model. These finding suggests that the target-molecule for melatonin can be Aβ oligomer, supporting the previous repots showing that a soluble Aβ assembly rather than the accumulation of amyloid plaques is sufficient to disrupt memory.
Consequently, above mentioned data led us to develop the monoclonal antibody specific to Aβ oligomer for the therapeutic intervention for Alzheimer's disease. After the tetramer bands cutted off immunized onto mice pad, we successfully obtained several monoclones which specifically immunoprecipitate Aβ oligomers. It is important to note that they do not cross-react to full-length amyloid precursor protein (APP), carboxyl-terminal derivatives of APP, or soluble Aβ monomer obtained from AD brain. We also found that our antibodies appear to be against "neurotoxic epitopes" and/or "assemblying epitopes", which can be explored as therapeutic antibody for Alzheimer's disease.
We are sure that neurotoxic Aβ oligomer-targeted therapy should be one of the most promising intervention therapy for Alzheimer's disease. Among them, immunodepletion and/or immunoneutralization of toxic Aβ oligomer using our antibodies will provide the most specific treatment for Alzheimer's disease.
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Research Products
(18 results)
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[Journal Article] Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides.2005
Author(s)
Nakaya Y, Yamane T, Shiraishi H, Wang HQ, Matsubara E, Sato T, Dolios G, Wang R, De Strooper B, Shoji M, Komano H, Yanagisawa K, Ihara Y, Fraser P, St George-Hyslop P, Nishimura M.
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Journal Title
J Biol Chem 280
Pages: 19070-19077
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Accumulation of Filamentous Tau in the Cerebral Cortex of Human Tau R406W Transgenic Mice.2005
Author(s)
Ikeda M, Shoji M, Kawarai T, Kawarabayashi T, Matsubara E, Murakami T, Sasaki A, Tomidokoro Y, Ikarashi Y, Kuribara H, Ishiguro K, Hasegawa M, Yen SH, Davies P, Chishti M A, Harigaya Y, Okamoto K, Abe K, Carlson GA, St.George-Hyslop P, Westaway D.
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Journal Title
Am J Pathol 166
Pages: 521-531
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Soluble Aβ homeostasis in AD and DS : impairment of anti-amyloidogenic protection by lipoproteins.2004
Author(s)
Matsubara E, Sekijima Y, Tokuda T, Urakami K, Amari M, Shizuka-Ikeda M, Tomidokoro Y, Ikeda M, Kawarabayashi T, Harigaya Y, Ikeda S, Murakami T, Abe K, Otomo B, Hirai S, Frangione B, Ghiso J, Shoji M.
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Journal Title
Neurobiol Aging 25
Pages: 833-841
Description
「研究成果報告書概要(欧文)」より
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