Elucidation of the molecular mechanisms of Abeta economy in the brain of Alzheimer's disease
| Project/Area Number |
17H04193
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | The University of Tokyo |
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Principal Investigator |
Iwatsubo Takeshi 東京大学, 大学院医学系研究科(医学部), 教授 (50223409)
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| Co-Investigator(Kenkyū-buntansha) |
山田 薫 東京大学, 大学院医学系研究科(医学部), 助教 (00735152)
若林 朋子 東京大学, 大学院医学系研究科(医学部), 特任助教 (20530330)
橋本 唯史 東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | アルツハイマー病 / Aβ / タウ / amyloid beta peptide / tau / 脳神経疾患 |
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| Outline of Final Research Achievements |
Massive deposition of amyloid β peptide (Aβ) as senile plaques is a pathological hallmark of Alzheimer’s disease (AD). In this study, we aimed to elucidate the molecular mechanisms of accumulation of Aβ and neurodegeneration in vivo in brains. We identified three Aβ-positive peaks by size-exclusion separation of soluble fractions of brains of APP transgenic mice. Among these peaks, we found that the ~200-300 kDa peak (peak 1 Aβ) is comprised of Aβ oligomers and had a potency to induce amyloid deposition upon injection into the brain paranchyma. We also found that targeted replacement of the mouse apolipoprotein E gene with the human apolipoprotein E3 suppressed the Aβ deposition induced by injection of peak 1 Aβ. Peak 1 Aβ was detected also in human AD brains. These findings should provide a clue to the mechanism of spatiotemporal spreading of Aβ in AD brains.
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| Academic Significance and Societal Importance of the Research Achievements |
認知症の原因疾患として増加するアルツハイマー病の病因として、脳内でアミロイドβ (Aβ)が凝集蓄積し、神経細胞の変性脱落を招く過程が重要と考えられているが、その詳細な分子機構は明らかでない。本研究ではアミロイド蓄積を有する脳内で、Aβは200-300 kDaのオリゴマー (peak 1 Aβ)を形成して存在すること、peak 1 Aβは脳内に注入するとAβ蓄積を誘発する能力を有することを明らかにした。 peak 1 Aβはアミロイド蓄積を介してアルツハイマー病の発症に関わる可能性があるため、その形成・作用機序を明らかにできれば、新たなアルツハイマー病予防・治療薬の開発に繋がるものと期待される。
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Report
(4 results)
Research Products
(21 results)
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[Journal Article] Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease.2019
Author(s)
Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, Hashimoto T, Mano A, Yamada K, Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T
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Journal Title
Mol. Neurodegener.
Volume: 14
Pages: 15-15
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Roles of collagen XXV and its putative receptors PTP s/d in intramuscular motor innervation and congenital cranial dysinnervation disorder2019
Author(s)
Haruka Munezane, Hiroaki Oizumi, Tomoko Wakabayashi, Shu Nishio, Tomoko Hirasawa, Takashi Sato, Akihiro Harada, Tomoyuki Yoshida, Takahiro Eguchi, Yuji Yamanashi, Tadafumi Hashimoto, Takeshi Iwatsubo
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Journal Title
Cell Reports
Volume: 29
Pages: 4362-4376
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Japanese and North American Alzheimer's Disease Neuroimaging Initiative studies: Harmonization for international trials.2018
Author(s)
Iwatsubo T, Iwata A, Suzuki K, Ihara R, Arai H, Ishii K, Senda M, Ito K, Ikeuchi T, Kuwano R, Matsuda H; Japanese Alzheimer's Disease Neuroimaging Initiative, Sun CK, Beckett LA, Petersen RC, Weiner MW, Aisen PS, Donohue MC; Alzheimer's Disease Neuroimaging Initiative
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Journal Title
Alzheimer's & Dementia
Volume: S1552-5260
Pages: 1077-1087
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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