Therapeutic potential of the anti-neurodegeneration effect of benign adipokines

• Project/Area Number: 25290019
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: HASHIMOTO Makoto 公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 副参事研究員 (50189502)
• Co-Investigator(Kenkyū-buntansha): 小柳 清光 信州大学, 医学部, 教授 (00134958)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2013: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: アディポネクチン / 神経変性疾患 / パーキンソン病 / αシヌクレイン / アルツハイマー病 / アディポネクチン (APN) / パーキンソン病 (PD) / シヌクレイノパチー / αシヌクレイン (αS) / β-シヌクレイン(βS) / APPL1 / シヌクレイン / 糖尿病

Outline of Final Research Achievements

Growing evidence suggests that neurodegenerative diseases are associated with metabolic disorders, but the mechanisms are still unclear. We investigated autopsy brain of α-synucleinopathies including Parkinson's disease and dementia with Lewy bodies, and analyzed the effects of adiponectin (APN) in cellular and in mouse models of α-synucleinopathies.
We observed that APN is localized in Lewy bodies derived from the brains of α-synucleinopathies. In neuronal cells expressing α-synuclein (αS), aggregation of αS was suppressed by treatment with recombinant APN in an AdipoRI-AMP kinase pathway-dependent manner. Concomitantly, phosphorylation and release of αS were significantly decreased by APN. In transgenic mice expressing αS, both histopathology and movement disorder were improved by intranasal treatment with globular APN.
Taken together, APN may suppress neurodegeneration through modification of the metabolic pathway in α-synucleinopathies.

Research Products

• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] Henan university(China)
• [Journal Article] Combined immunotherapy with “anti-insulin resistance” therapy as a novel therapeutic strategy against neurodegenerative diseases. (2016)
  • Author(s): Takamatsu Y, Ho G, Koike W, Sugama S, Takenouchi T, Waragai M, Wei J, Sekiyama K, Hashimoto M.
  • Journal Title: npj Parkinson’s Disease Volume: 3 Issue: 1 Pages: 4-4
  • DOI: 10.1038/s41531-016-0001-1
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Possible Involvement of Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer’s Disease. (2016)
  • Author(s): Waragai M, Adame A, Trinh I, Sekiyama K, Takamatsu Y, Une K, Masliah E, Hashimoto M
  • Journal Title: J Alzheimers Dis. Volume: in press Issue: 4 Pages: 1453-1459
  • DOI: 10.3233/jad-151116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Insight into the dissociation of behavior from histology in Synucleinopathies and in related neurodegenerative diseases (2016)
  • Author(s): Sekiyama K, Takamatsu Y, Koike W, Waragai M, Takenouchi T, Sugama S, Hashimoto M.
  • Journal Title: Journal of Alzheimer's Disease Volume: in press Issue: 3 Pages: 831-841
  • DOI: 10.3233/jad-151015
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease (2016)
  • Author(s): Sugama S, Sekiyama K, Kodama T, Takamatsu Y, Takenouchi T, Hashimoto M, Conti B, Kakinuma Y
  • Journal Title: Brain Behav Immun Volume: 51 Pages: 39-46
  • DOI: 10.1016/j.bbi.2015.08.015
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protection against neurodegenerative diseases on Earth and in space (2016)
  • Author(s): Takamatsu Y, Koike W, Takenouchi T, Sugama S, Waragai M, Wei J, Sekiyama K,Hashimoto M.
  • Journal Title: npj Microgravity Volume: 2 Issue: 1 Pages: 16013-16013
  • DOI: 10.1038/npjmgrav.2016.13
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Extracellular ATP induces P2X7 receptor activation in mouse Kupffer cells, leading to release of IL-1β, HMGB1, and PGE2, decreased MHC class I expression and necrotic cell death. (2015)
  • Author(s): Toki Y, Takenouchi T, Harada H, Tanuma S, Kitani H, Kojima S, Tsukimoto M.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 458(4) Issue: 4 Pages: 771-776
  • DOI: 10.1016/j.bbrc.2015.02.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role of α- and β-Synucleins in the Axonal Pathology of Parkinson's Disease and Related Synucleinopathies. (2015)
  • Author(s): Sekigawa A, Takamatsu Y, Sekiyama K, Hashimoto M.
  • Journal Title: Biomolecules. Volume: 5 Issue: 2 Pages: 1000-1011
  • DOI: 10.3390/biom5021000
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gaucher-Associated Parkinsonism. (2015)
  • Author(s): Li Y, Li P, Liang H, Zhao Z, Hashimoto M, Wei J.
  • Journal Title: Cell Mol Neurobiol. Volume: 35 (6) Issue: 6 Pages: 755-761
  • DOI: 10.1007/s10571-015-0176-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] シヌクレイントランスジェニックマウス (2015)
  • Author(s): 関山一成, 橋本 款.
  • Journal Title: 月刊 細胞 Volume: 47 (1) Pages: 16-19
• [Journal Article] Disease-Modifying Effect of Adiponectin in Model of α-Synucleinopathies. (2014)
  • Author(s): Sekiyama K, Waragai M, Akatsu H, Sugama S, Takenouchi T, Takamatsu Y, Fujita M, Sekigawa A, Rockenstein E, Inoue S, La Spada AR, Masliah E, Hashimoto M.
  • Journal Title: Ann Clin Transl Neurol. Volume: 1(7) Pages: 479-489
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of genomics in translational research for Parkinson's disease. (2014)
  • Author(s): Sekiyama, K., Takamatsu, Y., Waragai, M., Hashimoto, M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 452 (2) Issue: 2 Pages: 226-235
  • DOI: 10.1016/j.bbrc.2014.06.028
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inflammasome activation by danger signals: extracellular ATP and pH (2014)
  • Author(s): Takenouchi T, Tsukimoto M, Hashimoto M, Kitani H.
  • Journal Title: Inflammasome Volume: 1 (1) Pages: 2300-2312
  • Peer Reviewed
• [Journal Article] Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice (2014)
  • Author(s): Hagino Y., Kasai S, Masayo F, Setogawa S, Yamaura H,Yanagihara D, Hashimoto M, Kobayashi K, Meltzer H, Ikeda K
  • Journal Title: Neuropsychopharmacology Volume: - Issue: 5 Pages: 1-10
  • DOI: 10.1038/npp.2014.295
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dual effects of βsynuclein in the pathogenesis of Parkinson's disease (2013)
  • Author(s): Akio Sekigawa, Kazunari Sekiyama, Masayo Fujita, Yoshiki Takamatsu, Albert R. La Spada, Elizer Masliah, Makoto Hashimoto
  • Journal Title: Annals of Neurology Volume: 7 Issue: 2 Pages: 306-306
  • DOI: 10.1002/ana.23936
  • Peer Reviewed
• [Journal Article] Diversity of mitochondrial pathology in a mouse model of axonal degeneration in synucleinopathies (2013)
  • Author(s): Sekigawa A
  • Journal Title: Oxid Med Cell Longev. Volume: 2013 Pages: 817807-817807
  • DOI: 10.1155/2013/817807
  • Peer Reviewed
• [Journal Article] Biomarkers for the diagnosis and management of Parkinson's disease (2013)
  • Author(s): Waragai M, Sekiyama K, Fujita M, Tokuda T, Hashimoto M
  • Journal Title: Expert Opin Med Diagn Volume: 7 Issue: 1 Pages: 71-83
  • DOI: 10.1517/17530059.2013.733694
  • Peer Reviewed
• [Presentation] α及びβシヌクレインを共発現させたトランスジェニックフライモデルでの網羅的トランスクリプトーム解析 (2016)
  • Author(s): 高松芳樹、小池和佳子、本多芳子、児玉亨、井上聡、橋本款
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-01
• [Presentation] シヌクレイノパチーの病態に対する重力の影響 (2016)
  • Author(s): 橋本款、高松芳樹
  • Organizer: 第35回日本認知症学術集会
  • Place of Presentation: 東京国際フォ－ラム（東京都千代田区）
  • Year and Date: 2016-12-01
  • Invited
• [Presentation] Possible involvement of adiponectin in the pathogenesis of Alzheimer’s disease (2016)
  • Author(s): Hashimoto M. Takamatsu Y, Masliah E, Waragai M
  • Organizer: 第51回日本神経科学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-07-20
• [Presentation] αシヌクレインの蓄積がGM2ガングリオシドーシス病に与える影響 (2015)
  • Author(s): 鈴木 京子、山口 章、川島 真人、神崎 誠一、幸光 範子、勝瀬 大海、青木 直哉、都甲 崇、南澤 麿優覧、青木 一郎、橋本 款、山中 正二、平安 良雄
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際展示場（兵庫県・神戸市）
  • Year and Date: 2015-12-01
• [Presentation] レビー小体型認知症で同定された２種類の変異型βシヌクレイン（P123H、V70M）は、ショウジョウバエ脳において異なるメカニズムで神経変性を引き起こす (2015)
  • Author(s): 高松 芳樹、関山 一成、井上 聡、本多 芳子、児玉 亨、橋本 款
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際展示場（兵庫県・神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Disease Modifying Effect of Adiponectin in a Model of α-Synucleinopathies in Vitro and in Vivo. (2015)
  • Author(s): Masaaki Waragai, Kazunari Sekiyama, Yoshiki Takamatsu, Masayo Fujita, Akio Sekigawa, Naomichi Iwai, Edward Rockenstein, Satoshi Inoue, Albert R. La Spada, Elizer Masliah, Makoto Hashimoto
  • Organizer: Alzheimer's Association International Conference (AAIC2015)
  • Place of Presentation: Washington, USA
  • Year and Date: 2015-07-18
  • Int'l Joint Research
• [Presentation] Adiponectin, the anti-diabetic adipokine, has a therapeutic effect in models of α-synucleinopathies. (2015)
  • Author(s): Sekiyama, K., Waragai, M., Takamatsu, Y., Hashimoto, M.
  • Organizer: AD/PD 2015
  • Place of Presentation: Nice, France
  • Year and Date: 2015-03-19 – 2015-03-22
• [Presentation] 抗糖尿病因子；アディポネクチンを用いたパーキンソン病の発症前治療法の可能性 (2015)
  • Author(s): 橋本 款
  • Organizer: 第12回 RCGM フロンティア国際シンポジウム、サテライトミーティング
  • Place of Presentation: 埼玉医科大学ゲノムセンター
  • Year and Date: 2015-02-13
  • Invited
• [Presentation] アディポネクチンはα-シヌクレイノパチー細胞モデルのインスリンシグナルを亢進し神経変性の病態を改善する (2014)
  • Author(s): 関山 一成, 高松 芳樹, 橋本 款
  • Organizer: 第３７回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-09-11 – 2014-09-14
• [Presentation] レビー小体型認知症で見出された変異型βシヌクレインを発現するショウジョウバエは神経変性様表現型を示す (2014)
  • Author(s): 高松 芳樹, 関山 一成, 本多 芳子, 児玉 亨, 橋本 款
  • Organizer: 第３７回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-09-11 – 2014-09-14
• [Presentation] Parkin mutations impair mitochondrial function and enhance neurodegeneration in synucleinopathy associated with dementia with Lewy bodies (2014)
  • Author(s): 3.Wei, J., Yi Wang, Y., Wu, J., Wei, N., Li, P., Sekiyama, K., Fujita, M., Hashimoto, M.
  • Organizer: 第３７回日本神経科学大会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2014-09-11 – 2014-09-14
• [Presentation] シヌクレイノパチー病態におけるアディポネクチンの治療効果について. (2013)
  • Author(s): 関山 一成, 藤田 雅代, 高松 芳樹, 橋本 款.
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] レビー小体型認知症で同定された変異型β シヌクレイン(P123H, V70M) を導入したショウジョウバエの解析. (2013)
  • Author(s): 高松 芳樹，関川 明生，堀内 純二郎，関山 一成，藤田 雅代，児玉 亨，齋藤 実，橋本 款.
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] The anti-diabetic hormone, adiponectin, has protective effect on the pathogenesis of in vitro and in vivo models of α-synucleinopathies. (2013)
  • Author(s): Sekiyama K, Fujita M, Sekigawa A, Takamatsu Y, Hashimoto M.
  • Organizer: Neuroscinence 2013
  • Place of Presentation: San Diego USA
• [Book] 脳内環境辞典 (2017)
  • Author(s): 高松芳樹、小池和佳子、藁谷正明、杉野弘、橋本款
  • Total Pages: 2
  • Publisher: メディカルドゥ
• [Book] Role of autophagy in P2X7 receptor-mediated maturation and unconventional secretion of Il-1b in microglia Hayat, M. A. (Ed.) (2014)
  • Author(s): Takenouchi T, Sekiyama K Tsukimoto M, Iwamaru Y, Fujita M, Sugama S, Kitani H, *Hashimoto M.
  • Publisher: ISBN
• [Book] 「遺伝子治療・診断の最先端技術と新しい医薬品・診断薬の開発」 (2014)
  • Author(s): 高松 芳樹,関山 一成, 橋本 款
  • Publisher: 技術情報協会
• [Book] Ibuprofen: Clinical Pharmacology, Medical Uses and Adverse Effects. (2013)
  • Author(s): Sekiyama K, Fujita M, Sekigawa A, Takamatsu Y, Hashimoto M.
  • Publisher: InTech
• [Book] Emerging Drugs and Targets for Parkinson's Disease. (2013)
  • Author(s): Takenouchi T, Sekiyama K, Fujita M, Sugama S, Iwamaru Y, Kitani H, Hashimoto M.
  • Publisher: The Royal Society of Chemistry
• [Book] αシヌクレインの生理作用. (2013)
  • Author(s): 関山 一成, 高松 芳樹, 橋本 款
  • Publisher: 医学のあゆみ
• [Remarks] 公益財団法人 東京都医学総合研究所 パーキンソン病研究室
  • URL: http://www.igakuken.or.jp/parkinson/