Skip to main content

Advertisement

SpringerLink
Log in

Selective reduction of soluble Tau proteins in sporadic and familial frontotemporal dementias: an international follow-up study

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Recently, biochemical criteria were proposed to complement histological criteria for the diagnosis of dementia lacking distinctive histopathology (DLDH), the most common pathological variant of frontotemporal dementias (FTDs), based on evidence of a selective reduction of soluble tau proteins in brains from a large cohort of sporadic DLDH and hereditary FTD (HDDD2 family) patients. To ensure that these findings are not unique to the populations included in the initial report, we extended the previous work by analyzing 22 additional DLDH brains from the United States and international centers. Our biochemical analyses here confirmed the previous findings by demonstrating substantial reductions in soluble brain tau in gray and white matter of 14 cases and moderate reductions in 6 cases of DLDH. We also analyzed brain samples from an additional affected HDDD2 family member, and remarkably, unlike other previously studied members of this kindred, this patient's brain contained substantial amounts of pathological or insoluble tau. These findings confirm and extend the definition of DLDH as a sporadic or familial "tau-less" tauopathy with reduced levels of soluble brain tau and no insoluble tau or fibrillary tau inclusions, and the data also underline the phenotypic heterogeneity of HDDD2, which parallels the phenotypic heterogeneity of other hereditary neurodegenerative FTD tauopathies caused by tau gene mutations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

Similar content being viewed by others

References

  1. Adamec E, Chang HT, Stope EG, Hedreen JC, Vonsattel JP (2001) Tau protein expression in frontotemporal dementias. Neurosci Lett 315:21–24

    CAS  PubMed  Google Scholar 

  2. Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y (2001) α-Synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation. Brain Res 888:287–296

    PubMed  Google Scholar 

  3. Arnold SE (2000) Cellular and molecular pathology of the frontal dementias. In: Clark CM, Trojanowski JQ (eds) Neurodegenerative dementias: clinical features and pathological mechanisms, McGraw-Hill, New York, pp 291–301

    Google Scholar 

  4. Arnold SE, Clark CM, Grossman M, Han LY, Trojanowski JQ (2000) Quantitative neurohistological features of frontotemporal degeneration. Neurobiol Aging 21:913–919

    Article  CAS  PubMed  Google Scholar 

  5. Bigio EH, Brown DF, White CL 3rd (1999) Progressive supranuclear palsy with dementia: cortical pathology. J Neuropathol Exp Neurol 58: 359–364

    CAS  PubMed  Google Scholar 

  6. Boeve BF, Maraganore DM, Parisi JE, Ahlskog JE, Graff-Radford N, Caselli RJ, Dickson DW, Kokmen E, Petersen RC (1999) Pathologic heterogeneity in clinically diagnosed corticobasal degeneration Neurology 53: 795–800

    Google Scholar 

  7. Braak H, Braak E (1998) Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria J Neural Transm 105:801–819

    Article  CAS  Google Scholar 

  8. Brown J, Ashworth A, Gydesen S, Sorensen A, Rossor MN, Hardy J, Collinger J (1998) Familial non-specific dementia maps to chromosome 3. Hum Mol Genet 4:1625–1628

    Google Scholar 

  9. Brun A, England B, Gustavson L, Passant U, Neary D, Snowden JS (1994) Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57:416–418

    PubMed  Google Scholar 

  10. Crowther RA, Goedert M (2000) Abnormal tau-containing filaments in neurodegenerative disorders. J Struct Biol 130:271–279

    CAS  PubMed  Google Scholar 

  11. D'Souza I, Schellenberg GD (2000) Determinants of 4-repeat tau expression. Coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion. J Biol Chem 275:17700–17709

    Article  CAS  PubMed  Google Scholar 

  12. D'Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM-Y, Bird TD, Schellenberg GD (1999) Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA 96:5598–5603

    Article  CAS  PubMed  Google Scholar 

  13. Dickson DW (1998) Pick's disease: a modern approach. Brain Pathol 8:339–354

    CAS  PubMed  Google Scholar 

  14. Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM-Y, Trojanowski JQ (2002) Concurrence of α-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol 104:7–11

    Article  CAS  PubMed  Google Scholar 

  15. Feany MB, Dickson DW (1996) Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann Neurol 40:139–148

    CAS  PubMed  Google Scholar 

  16. Feany MB, Mattiace LA, Dickson DW (1996) Neuropathologic overlap of progressive supranuclear palsy, Pick's disease and corticobasal degeneration. J Neuropathol Exp Neurol 55:53–67

    CAS  PubMed  Google Scholar 

  17. Forman M, Zhukareva V, Bergeron C, Chin SS-M, Grossman M, Clark C, Lee VM-Y, Trojanowski JQ (2002) Signature tau neuropathology in gray and white matter of corticobasal degeneration. Am J Pathology 160:2045–2053

    CAS  Google Scholar 

  18. Forno LS, Langston JW, Herrick MK, Wilson JD, Murayama S (2002) Ubiquitin-positive neuronal and tau 2-positive glial inclusions in frontotemporal dementia of motor neuron type. Acta Neuropathol 103:599–606

    Article  CAS  PubMed  Google Scholar 

  19. Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, Pickering-Brown S, Duff K, Hutton M (1999) 5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem 274:15134–15143

    Article  CAS  PubMed  Google Scholar 

  20. Hasegawa M, Smith MJ, Goedert M (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 437:207–210

    Article  CAS  PubMed  Google Scholar 

  21. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BL, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VM-Y (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917

  22. Hong M, Trojanowski JQ, Lee VM-Y (2000) Tau-based Neurofibrillary Lesions. In: Clark CM, Trojanowski JQ (eds) Neurodegenerative dementias: clinical features and pathological mechanisms. McGraw-Hill, New York, pp 161–175

    Google Scholar 

  23. Hutton M, Lendon CL, Rizzi P, et al (1998) Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705

    CAS  PubMed  Google Scholar 

  24. Jellinger KA (1998) Dementia with grains (argyrophilic grain disease). Brain Pathol 8:377–386

    CAS  PubMed  Google Scholar 

  25. Knopman DS (1993) Overview of dementia lacking distinctive histology: pathological designation of a progressive dementia. Dementia 4:132–136

    CAS  PubMed  Google Scholar 

  26. Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T (1990) Dementia lacking distinctive histologic features: a common non-Alzheimer's degenerative dementia. Neurology 40:251–256

    CAS  PubMed  Google Scholar 

  27. Lee VM-Y, Wang J, Trojanowski JQ (1999) Purification of paired helical filament tau and normal tau from human brain tissue. Methods Enzymol 309:81–89

    CAS  PubMed  Google Scholar 

  28. Lee VM-Y, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    CAS  PubMed  Google Scholar 

  29. Lendon CL, Lynch T, Norton J, McKeel DW, Busfield F, Craddock N, Chakraverty S, Gopalakrishnan, Shears SD, Grimmet W, Wilhelmson KC, Hansen L, Morris JC, Goate AM (1998) Hereditary dysphasic disinhibition dementia. A frontotemporal dementia linked to 17q21-22. Neurology 50:1546–1555

    CAS  PubMed  Google Scholar 

  30. Lippa C, Zhukareva V, Kawrai T, Uryu K, Shafig M, Trojanowski JQ, Lee VM-Y (2000) Frontotemporal dementia with novel tau pathology and a Glu342Val tau mutation. Ann Neurol 48:850–858

    Article  CAS  PubMed  Google Scholar 

  31. Mann DMA, Pickering-Brown S (2001) The status of "Pick's disease" and other tauopathies within the frontotemporal dementias. Neurobiol Aging 22:109–111

    Article  PubMed  Google Scholar 

  32. Morris JC, Cole M, Banker BQ, Wright D (1984) Hereditary dysphasic dementia and the Pick-Alzheimer spectrum. Ann Neurol 16:455–466

    CAS  PubMed  Google Scholar 

  33. Mukaetova-Ladinska EB, Hurt J, Jakes R, Xuereb J, Honer WG, Wischik CM (2000) α-Synuclein inclusions in Alzheimer's and Lewy body diseases J Neuropathol Exp Neurol 59:408–417

    CAS  Google Scholar 

  34. Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M, Yen SH (1999) Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett 447:195–199

    Article  CAS  PubMed  Google Scholar 

  35. Neary D. Snowden JS, Gustavson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria. Neurology 51:546–1554

    Google Scholar 

  36. Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin VMD, Bruce J, Shuck T, Grossman M, Clark CM, Arnold S.E, Masliah E, Galasko D, Trojanowski J.Q, Lee VM-Y (2001) Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol 49:165–175

    CAS  PubMed  Google Scholar 

  37. Zhukareva V, Mann D, Pickering-Brown S, Uryu K, Shuck T, ShahK, Grossman M, Miller BL, Hulette CM, Feinstein SC, Trojanowski JQ, Lee VM-Y (2002) Sporadic Pick's disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 51:730–739

    Article  PubMed  Google Scholar 

  38. Zhukareva V, Shah K, Uryu K, Braak H, Del Tredici K, Sundarraj S, Clark C, Trojanowski JQ, VM-Y. Lee (2002) Biochemical analysis of tau proteins in argyrophilic grain disease, Alzheimer's disease and Pick's disease: a comparative study. Am J Pathology 161:1135–1141

    CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. J. Morris, Dr. V. Buckle, Dr. M. Frosch, J. Norton, MSN, RN, CS, and G. Tejada for their help in collecting tissue samples and patient information. We also thank the families of the patients, whose generosity makes this study possible. The National Institute of Aging and the Oxford Foundation (V.M.-Y.L.) provided support for this work.

Author information

Authors and Affiliations

  1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Maloney 3, HUP, 3600 Spruce Street, 19104-4283, Philadelphia, PA, USA

    Victoria Zhukareva, Sonali Sundarraj, John Q. Trojanowski & Virginia M.-Y. Lee

  2. Greater Manchester Neurosciences Centre, Manchester, UK

    David Mann

  3. Institute of Clinical Neuroscience, Department of Psychiatry, Sahlgrenska University Hospital-Mölndal, Mölndal, Sweden

    Magnus Sjogren & Kaj Blenow

  4. Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Christopher M. Clark

  5. Washington University Neuropathology Core, St. Louis, Missouri, USA

    Daniel W. McKeel & Alison Goate

  6. Drexel University School of Medicine, Philadelphia, Pennsylvania, USA

    Carol F. Lippa

  7. Columbia University, New York, New York, USA

    Jean-Paul Vonsattel

  8. Massachusetts General Hospital, Boston, Massachusetts, USA

    John H. Growdon

  9. Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    John Q. Trojanowski

Authors
  1. Victoria Zhukareva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonali Sundarraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Magnus Sjogren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaj Blenow
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christopher M. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel W. McKeel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alison Goate
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carol F. Lippa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Paul Vonsattel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John H. Growdon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John Q. Trojanowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Virginia M.-Y. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Virginia M.-Y. Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhukareva, V., Sundarraj, S., Mann, D. et al. Selective reduction of soluble Tau proteins in sporadic and familial frontotemporal dementias: an international follow-up study. Acta Neuropathol 105, 469–476 (2003). https://doi.org/10.1007/s00401-002-0668-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-002-0668-8

Keywords

Search

Navigation