Experimental research on the pathogenesis and pathophysiology of diseases that cause dementia

• Project/Area Number: 21591536
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: 財団法人東京都医学総合研究所 (2011); Tokyo Metropolitan Organization for Medical Research (2009-2010)
• Principal Investigator: AKIYAMA Haruhiko 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): HOSOKAWA Masato 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)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 老年精神医学 / 認知症 / プロテイノパチー / グラニュリン / アルツハイマー病 / タウ / TDP-43 / FUS / 前頭側頭葉変性症

Research Abstract

Accumulation of abnormal proteins in the brain, which is referred to as proteinopathy, is the essential feature of neurodegenerative diseases that cause dementia. Dissolution of the abnormal protein accumulation is a promising strategy to overcome such dementia disorders as Alzheimer's disease and frontotemporal lobar degeneration. The aim of this study is to investigate into the proteinopathy overlap, a yet unsolved issue in this field. We have analyzed immunohistochemically the postmortem brain tissues of neurodegenerative diseases from a view point of proteinopathy overlap. We also have made mouse models that carry at least two factors so that the models recapitulate aspects of the overlap.

Research Products

• [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
• [Journal Article] Biochemical increase in phosphorylated alpha-synuclein precedes histopathology of Lewy-type synucleinopathies (2012)
  • Author(s): Lue LF, Walker DG, Adler CH, Shill H, Tran H, Akiyama H, Sue LI, Caviness J, Sabbagh MN, Beach TG
  • Journal Title: Brain Pathol Volume: (in press) Issue: 6 Pages: 745-756
  • DOI: 10.1111/j.1750-3639.2012.00585.x
  • Peer Reviewed
• [Journal Article] Long-term oral intake of aluminium or zinc does not accelerate Alzheimer pathology in AβPP and AβPP/tau transgenic mice (2012)
  • Author(s): Akiyama H, Hosokawa M, Kametani F, Kondo H, Chiba M, Fukushima M, Tabira T
  • Journal Title: Neuropathology Volume: (in press) Issue: 4 Pages: 390-397
  • DOI: 10.1111/j.1440-1789.2011.01274.x
  • Peer Reviewed
• [Journal Article] Progressive nonfluent aphasia : A rare clinical subtype of FTLD-TDP in Japan (2012)
  • Author(s): Aoki N, Tsuchiya K, Kobayashi Z, Arai T, Togo T, Miyazaki H, Kondo H, Ishizu H, Uchikado H, Katsuse O, Hirayasu Y, Akiyama H
  • Journal Title: Neuropathology Volume: (in press) Issue: 3 Pages: 272-9
  • DOI: 10.1111/j.1440-1789.2011.01253.x
  • Peer Reviewed
• [Journal Article] Post mortem cerebrospinal fluidα-synuclein levels are raised in multiple system atrophy and distinguish this from the otherα-synucleinopathies, Parkinson's disease and Dementia with Lewy bodies (2012)
  • Author(s): Foulds PG, Yokota O, Thurston A, Davidson Y, Ahmed Z, Holton J, Thompson JC, Akiyama H, Arai T, Hasegawa M, Gerhard A, Allsop D, Mann DM
  • Journal Title: Neurobiol Dis Volume: 45 Issue: 1 Pages: 188-95
  • DOI: 10.1016/j.nbd.2011.08.003
  • Peer Reviewed
• [Journal Article] Epitope mapping of antibodies against TDP-43 and detection of protease-resistant fragments of pathological TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration (2011)
  • Author(s): Tsuji H, Nonaka T, Yamashita M, Suzukake M, Kametani F, Akiyama H, Mann D. M. A., Tamaoka A, Hasegawa M
  • Journal Title: Biochem Biophys Res Commun Volume: 417 Issue: 1 Pages: 116-121
  • DOI: 10.1016/j.bbrc.2011.11.066
  • Peer Reviewed
• [Journal Article] FALS with Gly72Ser mutation in SOD1 gene : Report of a family including the first autopsy case (2011)
  • Author(s): Kobayashi Z, Tsuchiy Kobayashi Z, Tsuchiya K, Kubodera T, Shibata N, Arai T, Miura H, Ishikawa C, Kondo H, Ishizu H, Akiyama H, Mizusawa H
  • Journal Title: Neurol Sci Volume: 300 Issue: 1-2 Pages: 9-13
  • DOI: 10.1016/j.jns.2010.10.030
  • NAID: 120007137590
  • Peer Reviewed
• [Journal Article] Molecular Dissection of TDP-43 Proteinopathies (2011)
  • Author(s): Hasegawa M, Nonaka T, Tsuji H, et al
  • Journal Title: J Mol Neurosci Volume: 45(3) Issue: 3 Pages: 480-5
  • DOI: 10.1007/s12031-011-9571-x
  • Peer Reviewed
• [Journal Article] Clinicopathological study of diffuse neurofibrillary tangles with calcification. With special reference to TDP-43 proteinopathy and alpha-synucleinopathy (2011)
  • Author(s): Habuchi C, Iritani S, Sekiguchi H, Torii Y, Ishihara R, Arai T, Hasegawa M, Tsuchiya K, Akiyama H, Shibayama H, Ozaki N
  • Journal Title: J Neurol Sci Volume: 301 Issue: 1-2 Pages: 77-85
  • DOI: 10.1016/j.jns.2010.10.021
  • Peer Reviewed
• [Journal Article] Effect of glycogen synthase kinase 3 β-mediated presenilin 1 phosphorylation on amyloid β production is negatively regulated by insulin receptor cleavage (2011)
  • Author(s): Maesako M, Uemura K, Kubota M, Hiyoshi K, Ando K, Kuzuya A, Kihara T, Asada M, Akiyama H, Kinoshita A
  • Journal Title: Neurosci Volume: 177 Pages: 298-307
  • DOI: 10.1016/j.neuroscience.2010.12.017
  • Peer Reviewed
• [Journal Article] Gray matter lesions in Nasu-Hakola disease : A report on three autopsy ca (2011)
  • Author(s): Aoki N, Tsuchiya K, Togo T, Kobayashi Z, Uchikado H, Katsuse O, Suzuki K, Fujishiro H, Arai T, Iseki E, Anno M, Kosaka K, Akiyama H, Hirayasu Y
  • Journal Title: Neuropathology Volume: 31 Issue: 2 Pages: 135-143
  • DOI: 10.1111/j.1440-1789.2010.01152.x
  • Peer Reviewed
• [Journal Article] Fatal Encephalitis in a Case of Hypereosinophilic Syndrome: MRI and Autopsy Findings (2011)
  • Author(s): Kobayashi Z, Tsuchiya K, Komachi H, Miki K, Yokota O, Arai T, Miake H, Ishizu H, Akiyama H, Mizusawa H
  • Journal Title: Internal Medicine Volume: 50 Issue: 11 Pages: 1219-1225
  • DOI: 10.2169/internalmedicine.50.4570
  • NAID: 130000770476
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Phosphorylated and cleaved TDP-43 in ALS/FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy (2010)
  • Author(s): Arai T, Hasegawa M, Nonoka T, et al
  • Journal Title: Neuropathology Volume: 30 Issue: 2 Pages: 170-181
  • DOI: 10.1111/j.1440-1789.2009.01089.x
  • Peer Reviewed
• [Journal Article] Argyrophilic grain disease with delusions and hallucinations : a pathological study (2010)
  • Author(s): Asaoka T, Tsuchiya K, Fujishiro H, Arai T, Hasegawa M, Akiyama H, Iseki E, Oda T, Onaya M, Tominaga I
  • Journal Title: Psychogeriatrics Volume: 10 Pages: 69-76
  • NAID: 10029770939
  • Peer Reviewed
• [Journal Article] Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease (2010)
  • Author(s): Coomaraswamy J, Kilger E, Wolfing H, Schafer C, Kaeser SA, Wegenast-Braun BM, Hefendehl JK, Wolburg H, Mazzella M, Ghiso J, Goedert M, Akiyama H, et al.[12番目/16名]
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Issue: 17 Pages: 7969-7974
  • DOI: 10.1073/pnas.1001056107
  • Peer Reviewed
• [Journal Article] Occurrence of basophilic inclusions and FUS-immunoreactive neuronal and glial inclusions in a case of familial amyotrophic lateral sclerosis (2010)
  • Author(s): Kobayashi Z, Tsuchiya K, Arai T, Aoki M, Hasegawa M, Ishizu H, Akiyama H, Mizusawa H
  • Journal Title: Neurol Sci Volume: 293 Issue: 1-2 Pages: 6-11
  • DOI: 10.1016/j.jns.2010.03.029
  • Peer Reviewed
• [Journal Article] Pseudopolyneuritic form of ALS revisited : clinical and pathological heterogeneity (2010)
  • Author(s): Kobayashi Z, Tsuchiya K, Arai T, Yokota O, Watabiki S, Ishizu H, Akiyama H, Mizusawa H
  • Journal Title: Neuropathology Volume: 30 Issue: 4 Pages: 372-380
  • DOI: 10.1111/j.1440-1789.2009.01084.x
  • Peer Reviewed
• [Journal Article] Clinicopathological characteristics of FTLD-TDP showing corticospinal tract degeneration but lacking lower motor neuron loss (2010)
  • Author(s): Kobayashi Z, Tsuchiya K, Arai T
  • Journal Title: J Neurol Sci Volume: 298 Issue: 1-2 Pages: 70-77
  • DOI: 10.1016/j.jns.2010.08.013
  • Peer Reviewed
• [Journal Article] Frontotemporal lobar degeneration with motor neuron disease showing severe and circumscribed atrophy of anterior temporal lobes (2010)
  • Author(s): Kuwahara H, Tsuchiya K, Saito Y, Kobayashi Z, Miyazaki H, Izumiyama Y, Akiyama H, Arai T, Mizusawa H
  • Journal Title: J Neurol Sci Volume: 297 Issue: 1-2 Pages: 92-96
  • DOI: 10.1016/j.jns.2010.07.004
  • Peer Reviewed
• [Journal Article] Familial ALS with G298S Mutation in TARDBP: A Comparison of CSF Tau Protein Levels with those in Sporadic ALS (2010)
  • Author(s): Nozaki I, Arai M, Takahashi K, Hamaguchi T, Yoshikawa H, Muroishi T, Noguchi-Shinohara M, Ito H, Itokawa M, Akiyama H, Kawata A, Yamada M
  • Journal Title: Internal Medicine Volume: 49 Issue: 12 Pages: 1209-1212
  • DOI: 10.2169/internalmedicine.49.3300
  • NAID: 130000251656
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] TDP-43 M337V Mutation in Familial Amyotrophic Lateral Sclerosis in Japan (2010)
  • Author(s): Tamaoka A, Arai M, Itokawa M, Arai T, Hasegawa M, Tsuchiya K, Takuma H, Tsuji H, Ishii A, Watanabe M, Takahashi Y, Goto J, Tsuji S, Akiyama H
  • Journal Title: Internal Medicine Volume: 49 Issue: 4 Pages: 331-334
  • DOI: 10.2169/internalmedicine.49.2915
  • NAID: 130000152618
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Effect of topographical distribution ofα-synuclein pathology on TDP-43 accumulation in Lewy body disease (2010)
  • Author(s): Yokota O, Davidson Y, Arai T, Hasegawa M, Akiyama H, Ishizu H, Terada S, Sikkink S, Pickering-Brown S, Mann DM
  • Journal Title: Acta Neuropathol Volume: 120 Issue: 6 Pages: 789-801
  • DOI: 10.1007/s00401-010-0731-9
  • Peer Reviewed
• [Journal Article] Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders (2010)
  • Author(s): Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, et al.[8番目/12名]
  • Journal Title: Acta Neuropathol Volume: 119 Issue: 6 Pages: 689-702
  • DOI: 10.1007/s00401-010-0664-3
  • Peer Reviewed
• [Journal Article] Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy (2010)
  • Author(s): Yokota O, Davidson Y, Bigio EH, Ishizu H, Terada S, Arai T, Hasegawa M, Akiyama H, Sikkink S, Pickering-Brown S, Mann DM
  • Journal Title: Acta Neuropathol Volume: 120 Issue: 1 Pages: 55-66
  • DOI: 10.1007/s00401-010-0702-1
  • Peer Reviewed
• [Journal Article] Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration : an update (2010)
  • Author(s): Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, et al.[16番目/21名]
  • Journal Title: Acta Neuropathol Volume: 119 Issue: 1 Pages: 1-4
  • DOI: 10.1007/s00401-009-0612-2
  • Peer Reviewed
• [Journal Article] Occurrence of basophilic inclusions and FUS-immunoreactive neuronal and glial inclusions in a case of familial amyotrophic lateral sclerosis (2010)
  • Author(s): Kobayashi Z, et al.
  • Journal Title: J Neurol Sci Volume: 293 Pages: 6-11
  • Peer Reviewed
• [Journal Article] Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease (2010)
  • Author(s): Yokota O, et al.
  • Journal Title: Acta Neuropathol Volume: 120 Pages: 789-801
  • Peer Reviewed
• [Journal Article] Unified staging system for lewy body disorders : Correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction (2009)
  • Author(s): Beach TG, Adler CH, Lue LF, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, White CL III, Akiyama H, et al.[13番目/18名]
  • Journal Title: Acta Neuropathol Volume: 117 Issue: 6 Pages: 613-634
  • DOI: 10.1007/s00401-009-0538-8
  • Peer Reviewed
• [Journal Article] TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases : a degenerative process distinct from normal ageing (2009)
  • Author(s): Davidson Y, Amin H, Kelley T, Shi J, Tian J, Kumaran R, Lashley T, Lees AJ, DuPlessis D, Neary D, Snowden J, Akiyama H, et al.[12番目/18名]
  • Journal Title: Acta Neuropathol Volume: 118 Issue: 3 Pages: 359-369
  • DOI: 10.1007/s00401-009-0526-z
  • Peer Reviewed
• [Journal Article] Plasma phosphorylated-TDP-43 protein levels correlate with brain pathology in frontotemporal lobar degeneration (2009)
  • Author(s): Foulds PG, Davidson Y, Mishra M, Hobson DJ, Humphreys KM, Taylor M, Johnson N, Weintraub S, Akiyama H, et al.[9番目/15名]
  • Journal Title: Acta Neuropathol Volume: 118 Issue: 5 Pages: 647-658
  • DOI: 10.1007/s00401-009-0594-0
  • Peer Reviewed
• [Journal Article] Identification of casein kinase-1 phosphorylation sites on TDP-43 (2009)
  • Author(s): Kametani F, Nonaka T, Suzuki T, Arai T, Dohmae N, Akiyama H, Hasegawa M
  • Journal Title: Biochem Biophys Res Commun Volume: 382 Issue: 2 Pages: 405-409
  • DOI: 10.1016/j.bbrc.2009.03.038
  • Peer Reviewed
• [Journal Article] Japanese encephalitis : serial CT findings and neuropathology in an autopsy case (2009)
  • Author(s): Kobayashi Z, Tsuchiya K, Yokota O, Haga C, Arai T, Akiyama H, Kotera M, Mizusawa H
  • Journal Title: Clin Neuropathol Volume: 28 Pages: 422-429
  • Peer Reviewed
• [Journal Article] Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43 (2009)
  • Author(s): Nonaka T, Kametani F, Arai T, Akiyama H, Hasegawa M
  • Journal Title: Hum Mol Genet Volume: 18 Issue: 18 Pages: 3353-3364
  • DOI: 10.1093/hmg/ddp275
  • Peer Reviewed
• [Journal Article] TDP-43 pathology in familial British dementia (2009)
  • Author(s): Schwab C, Arai T, Hasegawa M, Akiyama H, Yu S, McGeer PL
  • Journal Title: Acta Neuropathol Volume: 118 Issue: 2 Pages: 303-311
  • DOI: 10.1007/s00401-009-0514-3
  • Peer Reviewed
• [Journal Article] Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models (2009)
  • Author(s): Yamashita M, Nonaka T, Arai T, Kametani F, Buchman VL, Ninkina N, Bachurin SO, Akiyama H, Goedert M, Hasegawa M
  • Journal Title: FEBS Lett Volume: 583 Issue: 14 Pages: 2419-2424
  • DOI: 10.1016/j.febslet.2009.06.042
  • Peer Reviewed
• [Journal Article] Clinicopathological characterization of Pick's disease versus frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions (2009)
  • Author(s): Yokota O, Tsuchiya K, Arai T, Yagishita S, Matsubara O, Mochizuki A, Tamaoka A, Kawamura M, Yoshida H, Terada S, Ishizu H, Kuroda S, Akiyama H
  • Journal Title: Acta Neuropathol Volume: 117 Issue: 4 Pages: 429-444
  • DOI: 10.1007/s00401-009-0493-4
  • Peer Reviewed
• [Journal Article] TDP-43 pathology in familial British dementia (2009)
  • Author(s): Schwab C
  • Journal Title: Acta Neuropathol 118 Pages: 303-311
  • Peer Reviewed
• [Journal Article] Unified staging system for Lewy body disorders correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction (2009)
  • Author(s): Beach TG
  • Journal Title: Acta Neuropathol 117 Pages: 613-634
  • Peer Reviewed
• [Presentation] Progranulin reduction affects tau phosphorylation in P301L tau transgenic mice (2011)
  • Author(s): Hosokawa M, Arai T, Nonaka T, Yamashita M, Suzukake M, Matsuwaki T, Nishihara M, Hasegawa M, Akiyama H
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington D. C., USA
  • Year and Date: 2011-11-14
• [Presentation] Progranulin reduction affects tau phosphorylation in P301L tau transgenic mice (2011)
  • Author(s): Hosokawa M, Arai T, Nonaka T, Yamashita M, Suzukake M, Matsuwaki T, Nishihara M, Hasegawa M, Akiyama H
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington D.C.USA
  • Year and Date: 2011-11-14
• [Presentation] Quantitative determination of TDP-43 in cerebrospinal fluid of patients with amyotrophic lateral sclerosis and other neurodegenerative disorders (2011)
  • Author(s): Hosokawa M, Arai T, Yamashita M, Tsuji H, Nonaka T, Hasegawa M, Akiyama H
  • Organizer: International Conference on Alzheimer's Disease 2011
  • Place of Presentation: Paris France
  • Year and Date: 2011-07-17
• [Presentation] Screening for FUS proteinopathy in the institutional brain collection (2010)
  • Author(s): Akiyama H, Kobayashi Z, Arai T, Hosokawa M, Tsuchiya K, Yokota O, Shimomura Y, Kondo H, Haga C, Hasegawa M
  • Organizer: The 7th International Conference on Frontotemporal Dementias
  • Place of Presentation: Indianapolis, USA
  • Year and Date: 2010-10-06
• [Presentation] Neuroinflammation in the frontal cortex of patients with late-life depression (2010)
  • Author(s): Akiyama H, Arai T, Kondo H, Ikeda K, Beach TG
  • Organizer: The 17th International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
  • Year and Date: 2010-09-11
• [Presentation] アルツハイマー病およびレヴィー小体型認知症脳における progranulin の免疫組織化学的検討 (2009)
  • Author(s): 秋山治彦
  • Organizer: 第50回日本神経病理学会総会学術研究会
  • Place of Presentation: サンポートホール高松(高松市)
  • Year and Date: 2009-06-05
• [Presentation] リン酸化TDP43と神経原線維変化からみるグアム島の筋萎縮性側索硬化症(ALS)の本体について (2009)
  • Author(s): 橋本智代
  • Organizer: 第50回日本神経病理学会総会学術研究会
  • Place of Presentation: サンポートホール高松(高松市)
  • Year and Date: 2009-06-05
• [Presentation] TDP-43とALS:病理学的側面 (2009)
  • Author(s): 新井哲明
  • Organizer: 第50回日本神経病理学会総会学術研究会
  • Place of Presentation: サンポートホール高松(高松市)
  • Year and Date: 2009-06-04