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Elucidation of the molecular mechanisms of Abeta economy in the brain of Alzheimer's disease

Research Project

Project/Area Number 17H04193
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionThe University of Tokyo

Principal Investigator

Iwatsubo Takeshi  東京大学, 大学院医学系研究科(医学部), 教授 (50223409)

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)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
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)
Keywordsアルツハイマー病 / Aβ / タウ / amyloid beta peptide / tau / 脳神経疾患
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.

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。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report

Research Products

(21 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 6 results) Presentation (11 results) (of which Int'l Joint Research: 7 results,  Invited: 5 results) Remarks (1 results)

  • [Int'l Joint Research] Massachusetts General Hospital(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone species with higher molecular weight2019

    • Author(s)
      Bannai Taro、Mano Tatsuo、Chen Xigui、Ohtomo Gaku、Ohtomo Ryo、Tsuchida Takeyuki、Koshi-Mano Kagari、Hashimoto Tadafumi、Okazawa Hitoshi、Iwatsubo Takeshi、Tsuji Shoji、Toda Tatsushi、Iwata Atsushi
    • Journal Title

      Scientific Reports

      Volume: 9 Pages: 1-11

    • DOI

      10.1038/s41598-019-39494-7

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      Mol. Neurodegener.

      Volume: 14 Pages: 15-15

    • DOI

      10.1186/s13024-019-0315-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of the unique in vitro effects of unsaturated fatty acids on the formation of amyloid beta fibrils2019

    • Author(s)
      Miki Eto, Tadafumi Hashimoto, Takao Shimizu, Takeshi Iwatsubo
    • Journal Title

      PLOS One

      Volume: 14

    • DOI

      10.1371/journal.pone.0219465

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Seeding Activity-Based Detection Uncovers the Different Release Mechanisms of Seed-Competent Tau Versus Inert Tau via Lysosomal Exocytosis2019

    • Author(s)
      Yuki Tanaka, Kaoru Yamada, Kyoko Satake, Itaru Nishida, Matthias Heuberger, Tomoki Kuwahara, Takeshi Iwatsubo
    • Journal Title

      Frontiers in Neuroscience

      Volume: 13 Pages: 1258-1258

    • DOI

      10.3389/fnins.2019.01258

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
    • Journal Title

      Cell Reports

      Volume: 29 Pages: 4362-4376

    • DOI

      10.1016/j.celrep.2019.11.112

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Patterns and severity of vascular amyloid in Alzheimer’s disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer’s disease2018

    • Author(s)
      Mann David M. A.、Davidson Yvonne S.、Robinson Andrew C.、Allen Nancy、Hashimoto Tadafumi、Richardson Anna、Jones Matthew、Snowden Julie S.、Pendleton Neil、Potier Marie-Claude、Laquerri?re Annie、Prasher Vee、Iwatsubo Takeshi、Strydom Andre
    • Journal Title

      Acta Neuropathologica

      Volume: 136 Pages: 569-587

    • DOI

      10.1007/s00401-018-1866-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [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
    • Journal Title

      Alzheimer's & Dementia

      Volume: S1552-5260 Pages: 1077-1087

    • DOI

      10.1016/j.jalz.2018.03.009

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinical and cognitive characteristics of preclinical Alzheimer's disease in the Japanese Alzheimer's Disease Neuroimaging Initiative cohort2018

    • Author(s)
      Ihara Ryoko、Iwata Atsushi、Suzuki Kazushi、Ikeuchi Takeshi、Kuwano Ryozo、Iwatsubo Takeshi
    • Journal Title

      Alzheimer's & Dementia: Translational Research & Clinical Interventions

      Volume: 4 Pages: 645-651

    • DOI

      10.1016/j.trci.2018.10.004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] アルツハイマー病の予防・治療薬開発に向けて:研究の現況と社会・学術連携2020

    • Author(s)
      岩坪威
    • Organizer
      日本学術会議 学術フォーラム「認知症―予防と共生に向けて学術の取り組み」
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] アルツハイマー病の超早期治療と予防2019

    • Author(s)
      岩坪威
    • Organizer
      第30回日本医学会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] アルツハイマー病基礎研究の進歩2019

    • Author(s)
      岩坪威
    • Organizer
      第38回日本認知症学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Soluble high-molecular weight oligomers of amyloid-beta peptide derived from the brains of APP transgenic mice induce cerebral amyloid-beta deposits2019

    • Author(s)
      Tadafumi Hashimoto, Yasushi Naka, Kashiwagi-Hakozaki Mayu, Tomoya Tajiri, Takeshi Iwatsubo
    • Organizer
      Neuroscience2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characterization of the seed Abeta oligomers in the brains of APP transgenic mice2018

    • Author(s)
      Mayu Hakozaki-Kashiwagi, Yasushi Naka, Tomohiko Tajiri, Masashi Fukayama, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Organizer
      19th International Congress of Neuropathology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒト型とマウス型apolipoprotein EがAbeta脳内dynamicsに与える影響の相違2018

    • Author(s)
      粉川明日香、大野裕太郎、橋本唯史、岩坪威
    • Organizer
      第37回日本認知症学会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アミロイド斑蓄積のseedとして働く可溶性Abetaオリゴマーの同定2018

    • Author(s)
      箱崎眞結、仲泰史、田尻智也、深山正久、橋本唯史、岩坪威
    • Organizer
      第37回日本認知症学会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Alzheimer's disease:from molecular pathology to prevention2017

    • Author(s)
      Takeshi Iwatsubo
    • Organizer
      4th Federation of Asian-Oceanian neuroscience societies syposium
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] アルツハイマー病:超早期の治療に向けて2017

    • Author(s)
      岩坪 威
    • Organizer
      第52回日本成人病(生活習慣病)学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Characterization of the high molecular weight Abeta oligomers derived from the brains of APP transgenic mice2017

    • Author(s)
      Tadafumi Hashimoto, Yasushi Naka, Tomoya Tajiri, Mayu Hakozaki-Kashiwagi, Takeshi Iwatsubo
    • Organizer
      Neuroscience2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Differential effects of human and mouse apolipoprotein E on the metabolism and aggregation of amyloid-beta peptides2017

    • Author(s)
      Asuka Kokawa, Yutaro Ohno, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Organizer
      Neuroscience2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Remarks] リソソームストレス依存的にタウの細胞間伝播が亢進することを見出しました

    • URL

      http://www.neuropathology.m.u-tokyo.ac.jp/news.html#TanakaFront2019

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-12-27  

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