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Cited by 200Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau

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Taniguchi-Watanabe, Sayuri, Arai, Tetsuaki, Kametani, Fuyuki, Nonaka, Takashi, Masuda-Suzukake, Masami, Tarutani, Airi, Murayama, Shigeo, Saito, Yuko +7 more·2016·Acta Neuropathologica
DOI 10.1007/s00401-015-1503-3PMC PMC4713716
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Abstract

Intracellular filamentous tau pathology is the defining feature of tauopathies, which form a subset of neurodegenerative diseases. We have analyzed pathological tau in Alzheimer's disease, and in frontotemporal lobar degeneration associated with tauopathy to include cases with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and ones due to intronic mutations in MAPT. We found that the C-terminal band pattern of the pathological tau species is distinct for each disease. Immunoblot analysis of trypsin-resistant tau indicated that the different band patterns of the 7-18 kDa fragments in these diseases likely reflect different conformations of tau molecular species. Protein sequence and mass spectrometric analyses revealed the carboxyl-terminal region (residues 243-406) of tau comprises the protease-resistant core units of the tau aggregates, and the sequence lengths and precise regions involved are different among the diseases. These unique assembled tau cores may be used to classify and diagnose disease strains. Based on these results, we propose a new clinicopathological classification of tauopathies based on the biochemical properties of tau.

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  • The repeat region is a major contributor to the core structure of tau fibrils.

    “The repeat region is a major contributor to the core structure of tau fibrils (14, 15).”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [15]

  • Tau and MAP2 share significant sequence similarity in the microtubule binding repeats.

    “Tau and MAP2 share significant sequence similarity in the microtubule binding repeats (Fig. 1A), the same region that forms part of the core region of pathological tau filaments (15).”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [15]

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References 41 · Cited by 200

Research works printed but not linked: 38

  1. [1]Arai T Ikeda K Akiyama H Nonaka T Hasegawa M Ishiguro K Iritani S Tsuchiya K Iseki E Yagishita S Oda T Mochizuki A Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration Ann Neurol 2004 55 72 79 10.1002/ana.10793 14705114 · DOI
  2. [2]Arai T Ikeda K Akiyama H Shikamoto Y Tsuchiya K Yagishita S Beach T Rogers J Schwab C McGeer PL Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick’s disease, corticobasal degeneration and progressive supranuclear palsy Acta Neuropathol 2001 101 167 173 11271372
  3. [3]Arai T Ikeda K Akiyama H Tsuchiya K Iritani S Ishiguro K Yagishita S Oda T Odawara T Iseki E Different immunoreactivities of the microtubule-binding region of tau and its molecular basis in brains from patients with Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration Acta Neuropathol 2003 105 489 498 12677450
  4. [4]Arima K Ultrastructural characteristics of tau filaments in tauopathies: immuno-electron microscopic demonstration of tau filaments in tauopathies Neuropathology 2006 26 475 483 10.1111/j.1440-1789.2006.00669.x 17080728 · DOI
  5. [5]Brion JP Hanger DP Bruce MT Couck AM Flament-Durand J Anderton BH Tau in Alzheimer neurofibrillary tangles. N- and C-terminal regions are differentially associated with paired helical filaments and the location of a putative abnormal phosphorylation site Biochem J 1991 273 Pt 1 127 133 10.1042/bj2730127 1899184 PMC1150212 · DOI
  6. [6]Buee L Bussiere T Buee-Scherrer V Delacourte A Hof PR Tau protein isoforms, phosphorylation and role in neurodegenerative disorders Brain Res Brain Res Rev 2000 33 95 130 10.1016/S0165-0173(00)00019-9 10967355 · DOI
  7. [7]Clavaguera F Akatsu H Fraser G Crowther RA Frank S Hench J Probst A Winkler DT Reichwald J Staufenbiel M Ghetti B Goedert M Tolnay M Brain homogenates from human tauopathies induce tau inclusions in mouse brain Proc Natl Acad Sci USA 2013 110 9535 9540 10.1073/pnas.1301175110 23690619 PMC3677441 · DOI
  8. [9]Dan A Takahashi M Masuda-Suzukake M Kametani F Nonaka T Kondo H Akiyama H Arai T Mann DM Saito Y Hatsuta H Murayama S Hasegawa M Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain Acta Neuropathol Commun 2013 1 54 10.1186/2051-5960-1-54 24252707 PMC3893535 · DOI
  9. [10]Delacourte A Sergeant N Wattez A Gauvreau D Robitaille Y Vulnerable neuronal subsets in Alzheimer’s and Pick’s disease are distinguished by their tau isoform distribution and phosphorylation Ann Neurol 1998 43 193 204 10.1002/ana.410430209 9485060 · DOI
  10. [12]Gambetti P Cali I Notari S Kong Q Zou WQ Surewicz WK Molecular biology and pathology of prion strains in sporadic human prion diseases Acta Neuropathol 2011 121 79 90 10.1007/s00401-010-0761-3 21058033 PMC3077936 · DOI
  11. [13]Goedert M Clavaguera F Tolnay M The propagation of prion-like protein inclusions in neurodegenerative diseases Trends Neurosci 2010 33 317 325 10.1016/j.tins.2010.04.003 20493564 · DOI
  12. [14]Goedert M Crowther RA Spillantini MG Tau mutations cause frontotemporal dementias Neuron 1998 21 955 958 10.1016/S0896-6273(00)80615-7 9856453 · DOI · Paper page
  13. [15]Goedert M Spillantini MG Pathogenesis of the tauopathies J Mol Neurosci 2011 45 425 431 10.1007/s12031-011-9593-4 21785996 · DOI
  14. [16]Goedert M Spillantini MG Cairns NJ Crowther RA Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms Neuron 1992 8 159 168 10.1016/0896-6273(92)90117-V 1530909 · DOI
  15. [17]Hanger DP Byers HL Wray S Leung KY Saxton MJ Seereeram A Reynolds CH Ward MA Anderton BH Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis J Biol Chem 2007 282 23645 23654 10.1074/jbc.M703269200 17562708 · DOI · Paper page
  16. [18]Hasegawa M Watanabe A Takio K Suzuki M Arai T Titani K Ihara Y Characterization of two distinct monoclonal antibodies to paired helical filaments: further evidence for fetal-type phosphorylation of the tau in paired helical filaments J Neurochem 1993 60 2068 2077 10.1111/j.1471-4159.1993.tb03491.x 7684067 · DOI
  17. [19]Hasegawa M Watanabe S Kondo H Akiyama H Mann DM Saito Y Murayama S 3R and 4R tau isoforms in paired helical filaments in Alzheimer’s disease Acta Neuropathol 2014 127 303 305 10.1007/s00401-013-1191-9 24212601 PMC3895182 · DOI
  18. [20]Jakes R Novak M Davison M Wischik CM Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer’s disease EMBO J 1991 10 2725 2729 1915258 PMC452980
  19. [21]Kondo J Honda T Mori H Hamada Y Miura R Ogawara M Ihara Y The carboxyl third of tau is tightly bound to paired helical filaments Neuron 1988 1 827 834 10.1016/0896-6273(88)90130-4 2483105 · DOI
  20. [22]Ksiezak-Reding H Yen SH Structural stability of paired helical filaments requires microtubule-binding domains of tau: a model for self-association Neuron 1991 6 717 728 10.1016/0896-6273(91)90169-Z 1709023 · DOI
  21. [24]Luk KC Kehm V Carroll J Zhang B O’Brien P Trojanowski JQ Lee VM Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice Science 2012 338 949 953 10.1126/science.1227157 23161999 PMC3552321 · DOI · Paper page
  22. [25]Masuda-Suzukake M Nonaka T Hosokawa M Kubo M Shimozawa A Akiyama H Hasegawa M Pathological alpha-synuclein propagates through neural networks Acta Neuropathol Commun 2014 2 88 10.1186/s40478-014-0088-8 25095794 PMC4147188 · DOI
  23. [26]Masuda-Suzukake M Nonaka T Hosokawa M Oikawa T Arai T Akiyama H Mann DM Hasegawa M Prion-like spreading of pathological alpha-synuclein in brain Brain 2013 136 1128 1138 10.1093/brain/awt037 23466394 PMC3613715 · DOI · Paper page
  24. [27]Morishima-Kawashima M Hasegawa M Takio K Suzuki M Yoshida H Titani K Ihara Y Proline-directed and non-proline-directed phosphorylation of PHF-tau J Biol Chem 1995 270 823 829 10.1074/jbc.270.2.823 7822317 · DOI · Paper page
  25. [28]Nonaka T Masuda-Suzukake M Arai T Hasegawa Y Akatsu H Obi T Yoshida M Murayama S Mann DM Akiyama H Hasegawa M Prion-like properties of pathological TDP-43 aggregates from diseased brains Cell Rep 2013 4 124 134 10.1016/j.celrep.2013.06.007 23831027 · DOI
  26. [29]Nonaka T Watanabe ST Iwatsubo T Hasegawa M Seeded aggregation and toxicity of α-synuclein and tau: cellular models of neurodegenerative diseases J Biol Chem 2010 285 34885 34898 10.1074/jbc.M110.148460 20805224 PMC2966103 · DOI
  27. [30]Parchi P Cescatti M Notari S Schulz-Schaeffer WJ Capellari S Giese A Zou WQ Kretzschmar H Ghetti B Brown P Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease Brain 2010 133 3030 3042 10.1093/brain/awq234 20823086 PMC2947429 · DOI
  28. [31]Probst A Tolnay M Langui D Goedert M Spillantini MG Pick’s disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment Acta Neuropathol 1996 92 588 596 10.1007/s004010050565 8960316 · DOI
  29. [32]Sergeant N Wattez A Delacourte A Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms J Neurochem 1999 72 1243 1249 10.1046/j.1471-4159.1999.0721243.x 10037497 · DOI
  30. [33]Seubert P Mawal-Dewan M Barbour R Jakes R Goedert M Johnson GV Litersky JM Schenk D Lieberburg I Trojanowski JQ Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau J Biol Chem 1995 270 18917 18922 10.1074/jbc.270.32.18917 7642549 · DOI · Paper page
  31. [34]Spillantini MG Goedert M Tau mutations in familial frontotemporal dementia Brain 2000 123 Pt 5 857 859 10.1093/brain/123.5.857 10775532 · DOI
  32. [35]Takahashi M Miyata H Kametani F Nonaka T Akiyama H Hisanaga S Hasegawa M Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau Acta Neuropathol 2015 129 895 907 10.1007/s00401-015-1415-2 25869641 PMC4436700 · DOI
  33. [36]Uchihara T Tsuchiya K Nakamura A Akiyama H Silver staining profiles distinguish Pick bodies from neurofibrillary tangles of Alzheimer type: comparison between Gallyas and Campbell-Switzer methods Acta Neuropathol 2005 109 483 489 10.1007/s00401-005-0988-6 15759128 · DOI
  34. [37]Umeda Y Taniguchi S Arima K Piao YS Takahashi H Iwatsubo T Mann D Hasegawa M Alterations in human tau transcripts correlate with those of neurofilament in sporadic tauopathies Neurosci Lett 2004 359 151 154 10.1016/j.neulet.2004.01.060 15050686 · DOI · Paper page
  35. [38]von Bergen M Friedhoff P Biernat J Heberle J Mandelkow EM Mandelkow E Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure Proc Natl Acad Sci USA 2000 97 5129 5134 10.1073/pnas.97.10.5129 10805776 PMC25793 · DOI · Paper page
  36. [39]Wadsworth JD Collinge J Molecular pathology of human prion disease Acta Neuropathol 2011 121 69 77 10.1007/s00401-010-0735-5 20694796 PMC3015177 · DOI
  37. [40]Watanabe A Takio K Ihara Y Deamidation and isoaspartate formation in smeared tau in paired helical filaments. Unusual properties of the microtubule-binding domain of tau J Biol Chem 1999 274 7368 7378 10.1074/jbc.274.11.7368 10066801 · DOI
  38. [41]Wischik CM Novak M Thogersen HC Edwards PC Runswick MJ Jakes R Walker JE Milstein C Roth M Klug A Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease Proc Natl Acad Sci USA 1988 85 4506 4510 10.1073/pnas.85.12.4506 3132715 PMC280459 · DOI · Paper page

Authors
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, D. M. A., Iwatsubo, T., & Hasegawa, M.
Affiliations
  • University of Tsukuba (JP)
  • Tokyo Metropolitan Institute of Medical Science (JP)
  • Tokyo Metropolitan Institute of Gerontology (JP)
  • National Center of Neurology and Psychiatry (JP)
  • Aichi Medical University (JP)
  • University of Manchester (GB)
  • The University of Tokyo (JP)
Corresponding author
Hasegawa, Masato
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2015-11-04
Volume
131
Issue
2
Pages
267-280
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-015-1503-3
PMC
PMC4713716
OpenAlex
W2192012340
Cited by
200
References
41
Citations by year
2026: 9 · 2025: 4 · 2024: 24 · 2023: 22 · 2022: 14 · 2021: 27 · 2020: 24 · 2019: 27 · 2018: 20 · 2017: 14 · 2016: 14
FWCI
11.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Terrestrial Environment Research Center (University of Tsukuba) (submittedVersion, other-oa)
Funders
  • MEXT KAKENHI (23228004, 26117005, 15H02356)
  • MHLW (12946221)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
tauopathy, pathological tau, tau conformation, sarkosyl-insoluble tau, Alzheimer's disease, frontotemporal lobar degeneration, Pick bodies, corticobasal degeneration, progressive supranuclear palsy, C-terminal region, tau aggregates, clinicopathological classification
MeSH terms
Aged, Aged, 80 and over, Amino Acid Sequence, Brain, Brain Chemistry, Female, Humans, Male, Middle Aged, Protein Conformation, Sarcosine, Mass Spectrometry, Trypsin, Immunoblotting, Microscopy, Immunoelectron, tau Proteins, Sequence Analysis, Protein, Tauopathies

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