Pathological study of abnormal protein accumulation and its propagation in the brain of patients with dementia

• Project/Area Number: 24500429
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: AKIYAMA Haruhiko 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, 参事研究員 (20231839)
• Co-Investigator(Renkei-kenkyūsha): HASEGAWA Masato 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, 分野長 (10251232) ; HOSOKAWA Masato 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, 主席研究員 (00435116) ; ARAI Tetsuaki 筑波大学, 医学部精神科, 教授 (90291145)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 認知症 / 病理 / 異常蓄積蛋白 / 伝播 / 異常蛋白蓄積 / タウ

Outline of Final Research Achievements

The major cause of dementia is neurodegenerative diseases in which abnormally aggregated proteins form insoluble deposits in the brain. The distribution of these protein aggregates is consistent with the neuroanatomical architecture of the brain, a finding that suggests expansion of the lesions through the neural circuits. In Alzheimer’s disease, Abeta and tau are the principal proteins that are deposited in the brain. Tangle-predominant dementia (TPD) is characterized by heavy accumulation of tau in the limbic structures and virtual absence of Abeta. The nature of tau aggregates in TPD is similar to that in AD. We found that tau accumulation is much heavier in the nucleus accumbens in TPD than AD. In TPD, tau accumulation is heavier than AD in the hippocampal CA1 and the subiculum, the brain regions that give rise to significant projections to the nucleus accumbens. The finding supports a notion that the process of tau aggregation propagates through the neural circuits.

Research Products

• [Journal Article] The Abundance of Nonphosphorylated Tau in Mouse and Human Tauopathy Brains Revealed by the Use of Phos-Tag Method (2016)
  • Author(s): Kimura T, Hatsuta H, Masuda-Suzukake M, Hosokawa M, Ishiguro K, Akiyama H, Murayama S, Hasegawa M, Hisanaga S
  • Journal Title: American Journal of Pathology Volume: 186 Issue: 2 Pages: 398-409
  • DOI: 10.1016/j.ajpath.2015.10.009
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43. (2016)
  • Author(s): Nonaka T, Suzuki G, Tanaka Y, Kametani F, Hirai S, Okado H, Miyashita T, Saitoe M, Akiyama H, Masai H, Hasegawa M.
  • Journal Title: The journal of Biological Chemistry Volume: 291 Issue: 11 Pages: 5473-83
  • DOI: 10.1074/jbc.m115.695379
  • Peer Reviewed / Open Access
• [Journal Article] Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration. (2016)
  • Author(s): Kawakami I, Kobayashi Z, Arai T, Yokota O, Nonaka T, Aoki N, Niizato K, Oshima K, Higashi S, Katsuse O, Hosokawa M, Hasegawa M, Akiyama H.
  • Journal Title: Acta Neuropathol Commun Volume: 4 Issue: 1 Pages: 36-36
  • DOI: 10.1186/s40478-016-0304-9
  • NAID: 120007135517
  • Peer Reviewed / Open Access
• [Journal Article] Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. (2016)
  • Author(s): Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda-Suzukake M, Tarutani A, Murayama S, Saito Y, Arima K, Yoshida M, Akiyama H, Robinson A, Mann DM, Iwatsubo T, Hasegawa M.
  • Journal Title: Acta Neuropathol. Volume: 131(2) Issue: 2 Pages: 267-280
  • DOI: 10.1007/s00401-015-1503-3
  • NAID: 120007128537
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Feasibility Study: Comparison of Frontal Cortex Needle Core Versus Open Biopsy for Detection of Characteristic Proteinopathies of Neurodegenerative Diseases (2015)
  • Author(s): Serrano GE, Intorcia A, Carew J, Chiarolanza G, Hidalgo JA, Sue LI, Dugger BN, Saxon-LaBelle M, Filon J, Scroggins A, Pullen J, Fornwalt BE, Scott S, Sabbagh MN, Adler CH, Akiyama H, Beach TG
  • Journal Title: J Neuropathol Exp Neurol Volume: 74 Issue: 9 Pages: 934-942
  • DOI: 10.1097/nen.0000000000000235
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau. (2015)
  • Author(s): Takahashi M, Miyata H, Kametani F, Nonaka T, Akiyama H, Hisanaga SI, Hasegawa M.
  • Journal Title: Acta Neuropathol. Volume: 129 Issue: 6 Pages: 895-907
  • DOI: 10.1007/s00401-015-1415-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Progranulin reduction is associated with tau phosphorylation in P301L tau transgenic mice (2015)
  • Author(s): Hosokawa M, Arai T, Masuda-Suzukake M, Kondo H, Matsuwaki T, Nishihara M, Hasegawa M, Akiyama H
  • Journal Title: J Neuropahol Exp Neurol Volume: 74 Issue: 2 Pages: 158-165
  • DOI: 10.1097/nen.0000000000000158
  • Peer Reviewed
• [Journal Article] Pathological alpha-synuclein propagates through neural networks (2014)
  • Author(s): Masuda-Suzukake M, Nonaka T, Hosokawa M, Kubo M, Shimozawa A, Akiyama H, Hasegawa M
  • Journal Title: Acta Neuropathol Commun Volume: 2 Issue: 1 Pages: 88-88
  • DOI: 10.1186/preaccept-1296467154135944
  • Peer Reviewed / Open Access
• [Journal Article] Tau accumulation in the nucleus accumbens in tangle-predominant dementia (2014)
  • Author(s): Kawakami I, Hasegawa M, Arai T, Ikeda K, Oshima K, Niizato K, Aoki N, Katsuse O, Higashi S, Hosokawa M, Hirayasu Y, Akiyama H
  • Journal Title: Acta Neuropathol Volume: Commun 2 Issue: 1 Pages: 40-40
  • DOI: 10.1186/2051-5960-2-40
  • Peer Reviewed / Open Access
• [Journal Article] Distinct pathways leading to TDP-43-induced cellular dysfunctions. (2014)
  • Author(s): Yamashita M, Nonaka T, Hirai S, Miwa A, Okado H, Arai T, Hosokawa M, Akiyama H, Hasegawa M.
  • Journal Title: Hum Mol Genet. Volume: 23 Issue: 16 Pages: 4345-56
  • DOI: 10.1093/hmg/ddu152
  • Peer Reviewed / Open Access
• [Journal Article] 3R and 4R tau isoforms in paired helical filaments in Alzheimer's disease. (2014)
  • Author(s): Hasegawa, M., S. Watanabe, H. Kondo, H. Akiyama, D. M. Mann, Y. Saito and S. Murayama
  • Journal Title: Acta Neuropathol Volume: 127 Issue: 2 Pages: 303-305
  • DOI: 10.1007/s00401-013-1191-9
  • Peer Reviewed
• [Journal Article] An Autopsy case of concurrent Huntington’s disease and neurofibromatosis type 1. (2014)
  • Author(s): Kawakami I, Katsuse O, Aoki N, Togo T, Suzuki K, Isojima D, Kondo D, Iseki E, Kosaka K, Akiyama H, Hirayasu Y
  • Journal Title: Psychogeriatrics Volume: 14 Issue: 1 Pages: 81-86
  • DOI: 10.1111/psyg.12040
  • Peer Reviewed
• [Journal Article] Differential diagnosis of amyotrophic lateral sclerosis from Guillain-Barré syndrome by quantitative determination of TDP-43 in cerebrospinal fluid. (2014)
  • Author(s): Hosokawa M, Arai T, Yamashita M, Tsuji H, Nonaka T, Masuda-Suzukake M, Tamaoka A, Hasegawa M, Akiyama H.
  • Journal Title: Int. J. Neurosci. Volume: 124 Issue: 5 Pages: 344-349
  • DOI: 10.3109/00207454.2013.848440
  • Peer Reviewed
• [Journal Article] Submandibular gland needle biopsy for the diagnosis of Parkinson disease (2014)
  • Author(s): Adler CH, Dugger BN, Hinni ML, Lott DG, Driver-Dunckley E, Hidalgo J, Henry-Watson J, Serrano G, Sue LI, Nagel T, Duffy A, Shill HA, Akiyama H, Walker DG, *Beach TG
  • Journal Title: Neurology Volume: 82 Issue: 10 Pages: 858-864
  • DOI: 10.1212/wnl.0000000000000204
  • Peer Reviewed
• [Journal Article] Prion-like spreading of pathological alpha-synuclein in brain. (2013)
  • Author(s): Masuda-Suzukake M, Nonaka T, Hosokawa M., Oikawa T, Arai T, Akiyama H, Mann D, Hasegawa M
  • Journal Title: Brain Volume: 136 Issue: 4 Pages: 1128-38
  • DOI: 10.1093/brain/awt037
  • Peer Reviewed
• [Journal Article] Prion-like Properties of Pathological TDP-43 Aggregates from Diseased Brains. (2013)
  • Author(s): Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, Hasegawa M.
  • Journal Title: Cell Rep. Volume: 4 Issue: 1 Pages: 124-34
  • DOI: 10.1016/j.celrep.2013.06.007
  • Peer Reviewed
• [Journal Article] Pathological features of FTLD-FUS in a Japanese population: Analyses of nine cases. (2013)
  • Author(s): Kobayashi Z, Kawakami I, Arai T, Yokota O, Tsuchiya K, Kondo H, Shimomura Y, Haga C, Aoki N, Hasegawa M, Hosokawa M, Oshima K, Niizato K, Ishizu H, Terada S, Onaya M, Ikeda M, Oyanagi K, Nakano I, Murayama S, Akiyama H, Mizusawa H.
  • Journal Title: Neurol. Sci. Volume: 335 Issue: 1-2 Pages: 89-95
  • DOI: 10.1016/j.jns.2013.08.035
  • Peer Reviewed
• [Journal Article] Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain. (2013)
  • Author(s): Dan A, Takahashi M, Masuda-Suzukake M, Kametani F, Nonaka T, Kondo H, Akiyama H, Arai T, Mann DMA, Saito Y, Hatsuta H, Murayama S, Hasegawa M.
  • Journal Title: Acta Neuropathol. Commun. Volume: 1 Issue: 1 Pages: 54-54
  • DOI: 10.1186/2051-5960-1-54
  • Peer Reviewed
• [Journal Article] Atypical FTLD-FUS associated with ALS-TDP : a case report (2013)
  • Author(s): Kobayashi Z, Arai T, Yokota O, Tsuchiya K, Hosokawa M, Oshima K, Niizato K, Akiyama H, Mizusawa H
  • Journal Title: Neuropathology Volume: 33 Issue: 1 Pages: 83-86
  • DOI: 10.1111/j.1440-1789.2012.01325.x
  • Peer Reviewed
• [Journal Article] Methylene blue reduced abnormal tau accumulation in P301L tau transgenic mice. (2012)
  • Author(s): Hosokawa M
  • Journal Title: PLoS One Volume: 7 Issue: 12 Pages: e52389-e52389
  • DOI: 10.1371/journal.pone.0052389
  • Peer Reviewed
• [Journal Article] Molecular analysis and biochemical classification of TDP-43 proteinopathy (2012)
  • Author(s): Tsuji H
  • Journal Title: Brain Volume: 135(11) Issue: 11 Pages: 3380-91
  • DOI: 10.1093/brain/aws230
  • Peer Reviewed
• [Journal Article] Localization of fused in sarcoma(FUS) protein to the post synaptic density in the brain (2012)
  • Author(s): Aoki N, Higashi S, Kawakami I, Kobayashi Z, Hosokawa M, Katsuse O, Togo T, Hirayasu Y, Akiyama H
  • Journal Title: Acta Neuropathol Volume: (in press) Issue: 3 Pages: 383-94
  • DOI: 10.1007/s00401-012-0984-6
  • Peer Reviewed
• [Presentation] グラニュリン変異脳における神経変性疾患関連タンパク質の重複蓄積 (2015)
  • Author(s): 細川雅人，新井哲明，近藤ひろみ，長谷川成人，秋山治彦
  • Organizer: 第34回日本認知症学会
  • Place of Presentation: リンクステーション青森（青森県青森市）
  • Year and Date: 2015-10-02
• [Presentation] 神経細胞と脳の炎症 (2014)
  • Author(s): 秋山治彦
  • Organizer: 第33回日本認知症学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-11-29
  • Invited
• [Presentation] タウP301L変異が確認されたFTDP-17の1例 (2014)
  • Author(s): 鈴木寿臣，女屋光基，野島照雄，冨永格，織田辰郎，三村將，小林智則，長谷川成人，秋山治彦
  • Organizer: 第55回日本神経病理学会
  • Place of Presentation: 一橋講堂（東京都）
  • Year and Date: 2014-06-07
• [Presentation] 本邦におけるbehavioral variant of frontotemporal dementia (bvFTD) 35例の臨床 (2014)
  • Author(s): 小林 禅，河上 緒，新井哲明，横田修，大島健一，新里和弘，秋山治彦，水澤英洋
  • Organizer: 第55回日本神経病理学会
  • Place of Presentation: 一橋講堂（東京都）
  • Year and Date: 2014-06-06
• [Presentation] 外傷性脳損傷の脳における神経変性疾患関連たんぱく質の凝集体分布の検討 (2014)
  • Author(s): 東 晋二，羽賀千恵，河上緒，長谷川成人，大島健一，新里和弘，女屋光基，秋山治彦
  • Organizer: 第55回日本神経病理学会
  • Place of Presentation: 一橋講堂（東京都）
  • Year and Date: 2014-06-06
• [Presentation] AD脳に蓄積するタウの解析 (2014)
  • Author(s): 長谷川成人，近藤ひろみ，齊藤祐子，初田裕幸，村山繁雄，秋山治彦
  • Organizer: 第55回日本神経病理学会
  • Place of Presentation: 一橋講堂（東京都）
  • Year and Date: 2014-06-06
• [Presentation] アルツハイマー病脳における神経炎症
  • Author(s): 秋山治彦，下村洋子，近藤ひろみ，羽賀千恵，細川雅人
  • Organizer: 日本認知症学会
  • Place of Presentation: 松本市
  • Invited
• [Presentation] 認知症の基礎と臨床
  • Author(s): 秋山治彦
  • Organizer: 日本脳神経外科学会
  • Place of Presentation: 横浜市
  • Invited
• [Presentation] Localization of Fused in Sarcoma (FUS) Protein to the Post Synaptic Density in the Brain
  • Author(s): Akiyama H, Aoki N, Higashi S, Kawakami I, Kobayashi Z, Hosokawa M, Togo T, Hirayasu Y
  • Organizer: 8th International Conference on FTD
  • Place of Presentation: Manchester, UK
• [Presentation] Progranulin reduction affects tau phosphorylation in P301L tau transgenic mice
  • Author(s): Hosokawa M, Arai T, Masuda-Suzukake M, Nonaka T, Yamashita M, Matsuwaki T, Nishihara M, Hasegawa M, Akiyama H
  • Organizer: The 11th International Conference on Alzheimer's and Parkinson's Diseases
  • Place of Presentation: Firenze, Italy.
• [Presentation] Three Autopsy Cases of FTD-MND with Progressive Aphasia
  • Author(s): Kawakami I, Higashi S, Aoki N, Niizato K, Oshima K, Katsuse O, Togo T, Kobayashi Z, Hosokawa M, Tsuji H, Tamaoka A, Hasegawa M, Arai T, Tsuchiya K, Hirayasu Y, Akiyama H
  • Organizer: 8th International Conference on FTD
  • Place of Presentation: Manchester, UK
• [Presentation] 老年期発症の幻覚妄想を認め，辺縁系に高度タウ病変を呈した3剖検例
  • Author(s): 河上緖，新井哲明，池田研二，大島健一，新里和弘，東晋二，青木直哉，水上勝義，平安良雄，秋山治彦
  • Organizer: 第31回日本認知症学会
  • Place of Presentation: つくば
• [Presentation] 進行性失語が前景に立った運動ニューロン疾患を伴う前頭側頭型認知症の二剖検例
  • Author(s): 河上緖，東晋二，青木直哉，新里和弘，大島健一，安野みどり，羽賀千恵，下村洋子，鈴木京子，勝瀬大海，都甲崇，小林禅，辻浩史，玉岡晃，長谷川成人，新井哲明，土谷邦秋，平安良雄，秋山治彦
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Remarks] 公益財団法人東京都医学総合研究所
  • URL: http://www.igakuken.or.jp/index.html