Acta Neuropathologica

, Volume 118, Issue 2, pp 303–311 | Cite as

TDP-43 pathology in familial British dementia

  • Claudia Schwab
  • Tetsuaki Arai
  • Masato Hasegawa
  • Haruhiko Akiyama
  • Sheng Yu
  • Patrick L. McGeerEmail author
Case Report


Trans-activation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. This has suggested defining a new class of diseases known as TDP-43 proteinopathies. However, it has been reported more recently that TDP-43 positive inclusions occur in other neurodegenerative disorders such as Alzheimer’s disease, Dementia with Lewy Bodies and Parkinsonism dementia complex of Guam. Here we report the occurrence of TDP-43 inclusions in one other neurodegenerative disorder: familial British dementia. Using a variety of antibodies against phosphorylated and non-phosphorylated TDP-43 epitopes, we found intense accumulation occurred in the form of dystrophic neurites, neuronal cytoplasmic inclusions and was also occasionally associated with neurofibrillary tangles. Double immunostaining revealed that TDP-43 and tau aggregates were rarely directly colocalized, but co-existed in the same neurons as separate inclusions. Double staining with ubiquitin showed a direct colocalization with TDP-43. The phosphorylation-dependent TDP-43 antibodies proved superior to phosphorylation-independent antibodies in revealing pathological inclusions since the former did not stain non-phosphorylated TDP-43 in normal nuclei. Our results support the concept that TDP-43 pathology is not narrowly restricted, but is involved in the etiology of many neurodegenerative disorders.


TDP-43 Familial British dementia ABri Ubiquitin Intracellular inclusions Phosphorylation-dependent TDP-43 antibodies 



We greatly appreciate the expert support with confocal imaging of Dr. Henry G. S. Martin (Vancouver, Canada). This research was supported by the Pacific Alzheimer Research Foundation.

Conflict of interest statement

The authors declare that they have no conflict of interest.


  1. 1.
    Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445PubMedCrossRefGoogle Scholar
  2. 2.
    Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRefGoogle Scholar
  3. 3.
    Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136PubMedCrossRefGoogle Scholar
  4. 4.
    Buratti E, Baralle FE (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J Biol Chem 276:36337–36343PubMedCrossRefGoogle Scholar
  5. 5.
    Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13:867–878PubMedCrossRefGoogle Scholar
  6. 6.
    Forman MS, Trojanowski JQ, Lee VM (2007) TDP-43: a novel neurodegenerative proteinopathy. Curr Opin Neurobiol 17:548–555PubMedCrossRefGoogle Scholar
  7. 7.
    Freeman SH, Spires-Jones T, Hyman BT, Growdon JH, Frosch MP (2008) TAR-DNA binding protein 43 in Pick disease. J Neuropathol Exp Neurol 67:62–67PubMedCrossRefGoogle Scholar
  8. 8.
    Fujishiro H, Uchikado H, Arai T et al (2009) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158PubMedCrossRefGoogle Scholar
  9. 9.
    Geser F, Winton MJ, Kwong LK et al (2008) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145PubMedCrossRefGoogle Scholar
  10. 10.
    Griffiths RA, Mortimer TF, Oppenheimer DR, Spalding JM (1982) Congophilic angiopathy of the brain: a clinical and pathological report on two siblings. J Neurol Neurosurg Psychiatry 45:396–408PubMedCrossRefGoogle Scholar
  11. 11.
    Hasegawa M, Arai T, Akiyama H et al (2007) TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain 130:1386–1394PubMedCrossRefGoogle Scholar
  12. 12.
    Hasegawa M, Arai T, Nonaka T et al (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70PubMedCrossRefGoogle Scholar
  13. 13.
    Higashi S, Iseki E, Yamamoto R et al (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294PubMedCrossRefGoogle Scholar
  14. 14.
    Holton JL, Ghiso J, Lashley T et al (2001) Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. Am J Pathol 158:515–526PubMedGoogle Scholar
  15. 15.
    Hu WT, Josephs KA, Knopman DS et al (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220PubMedCrossRefGoogle Scholar
  16. 16.
    Igaz LM, Kwong LK, Xu Y et al (2008) Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol 173:182–194PubMedCrossRefGoogle Scholar
  17. 17.
    Inukai Y, Nonaka T, Arai T et al (2008) Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS. FEBS Lett 582:2899–2904PubMedCrossRefGoogle Scholar
  18. 18.
    Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ (2007) TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathol 114:63–70PubMedCrossRefGoogle Scholar
  19. 19.
    Mackenzie IR, Baborie A, Pickering-Brown S et al (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549PubMedCrossRefGoogle Scholar
  20. 20.
    Mackenzie IR, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18PubMedCrossRefGoogle Scholar
  21. 21.
    Miklossy J, Steele JC, Yu S et al (2008) Enduring involvement of tau, beta-amyloid, alpha-synuclein, ubiquitin and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS/PDC). Acta Neuropathol 116:625–637PubMedCrossRefGoogle Scholar
  22. 22.
    Nakashima-Yasuda H, Uryu K, Robinson J et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229PubMedCrossRefGoogle Scholar
  23. 23.
    Neumann M, Kwong LK, Lee EB et al (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149PubMedCrossRefGoogle Scholar
  24. 24.
    Neumann M, Mackenzie IR, Cairns NJ et al (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157PubMedCrossRefGoogle Scholar
  25. 25.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  26. 26.
    Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69:3584–3596PubMedGoogle Scholar
  27. 27.
    Oyanagi K, Makifuchi T, Ohtoh T, Chen KM, Gajdusek DC, Chase TN (1997) Distinct pathological features of the gallyas- and tau-positive glia in the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. J Neuropathol Exp Neurol 56:308–316PubMedCrossRefGoogle Scholar
  28. 28.
    Plant GT, Revesz T, Barnard RO, Harding AE, Gautier-Smith PC (1990) Familial cerebral amyloid angiopathy with nonneuritic amyloid plaque formation. Brain 113:721–747PubMedCrossRefGoogle Scholar
  29. 29.
    Schnell SA, Staines WA, Wessendorf MW (1999) Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem 47:719–730PubMedGoogle Scholar
  30. 30.
    Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL (2008) Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J Neuropathol Exp Neurol 67:1159–1165PubMedCrossRefGoogle Scholar
  31. 31.
    Schwab C, Hosokawa M, Akiyama H, McGeer PL (2003) Familial British dementia: colocalization of furin and ABri amyloid. Acta Neuropathologica 106:278–284PubMedCrossRefGoogle Scholar
  32. 32.
    Strong MJ, Volkening K, Hammond R et al (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35:320–327PubMedCrossRefGoogle Scholar
  33. 33.
    Uryu K, Nakashima-Yasuda H, Forman MS et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564PubMedCrossRefGoogle Scholar
  34. 34.
    Vidal R, Frangione B, Rostagno A et al (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399:776–781PubMedCrossRefGoogle Scholar
  35. 35.
    Worster-Drought C, Hill TR, McEnemey WH (1933) Familial presenile dementia with spastic paralysis. J Neurol Psychopathol 14:27–34CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Claudia Schwab
    • 1
  • Tetsuaki Arai
    • 2
  • Masato Hasegawa
    • 3
  • Haruhiko Akiyama
    • 2
  • Sheng Yu
    • 1
  • Patrick L. McGeer
    • 1
    Email author
  1. 1.Department of Psychiatry, Kinsmen Laboratory of Neurological ResearchUniversity of British ColumbiaVancouverCanada
  2. 2.Department of Psychogeriatrics, Tokyo Institute of PsychiatryTokyo Metropolitan Organization for Medical ResearchTokyoJapan
  3. 3.Department of Molecular Neurobiology, Tokyo Institute of PsychiatryTokyo Metropolitan Organization for Medical ResearchTokyoJapan

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