Acta Neuropathologica

, Volume 117, Issue 5, pp 583–589 | Cite as

Evidence for abnormal tau phosphorylation in early aggressive multiple sclerosis

  • Jane Marian Anderson
  • Rickie Patani
  • Richard Reynolds
  • Richard Nicholas
  • Alastair Compston
  • Maria Grazia Spillantini
  • Siddharthan Chandran
Case Report

Abstract

Although progression in multiple sclerosis is pathologically dominated by neurodegeneration, the underlying mechanism is unknown. Abnormal hyperphosphorylation of tau is implicated in the aetiopathogenesis of some common neurodegenerative disorders. We recently demonstrated the association of insoluble tau with established secondary progressive MS, raising the hypothesis that its accumulation is relevant to disease progression. In order to begin to determine the temporal emergence of abnormal tau with disease progression in MS, we examined tau phosphorylation in cerebral tissue from a rare case of early aggressive MS. We report tau hyperphosphorylation occurring in multiple cell types, with biochemical analysis confirming restriction to the soluble fraction. The absence of sarcosyl-insoluble tau fraction in early disease and its presence in secondary progression raises the possibility that insoluble tau accumulates with disease progression.

Keywords

Tau Acute inflammatory demyelinating disease Experimental autoimmune encephalomyelitis Axonopathy Neuronal loss 

Abbreviations

CNS

Central nervous system

LFB

Luxol fast blue

mAb

Monoclonal antibody

NGS

Normal goat serum

PB

Phosphate buffer

PBS

Phosphate buffered saline

TX-PBS

Triton-phosphate buffered saline

Supplementary material

401_2009_515_MOESM1_ESM.tif (1.5 mb)
Immunohistochemical and histological characterisation of control fronto-parietal tissue with no known neuropathological disease. Normal myelin staining (LFB) of a white matter tract flanked by grey matter is shown. Inset demonstrates a representative high powered image of microglia immunolabelled with HLA-DR/LN-3, which sparsely populate healthy cerebral tissue. The resting ramified state shown is in contrast to the amoeboid morphology seen in active multiple sclerosis lesions (Fig 1c). Scale bars: main image:1mm; inset: 50μm. (TIFF 1504 kb)

References

  1. 1.
    Adams CW, Poston RN, Buk SJ (1989) Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J Neurol Sci 92:291–306. doi:10.1016/0022-510X(89)90144-5 PubMedCrossRefGoogle Scholar
  2. 2.
    Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, Atzori C, Migheli A, Crowther RA, Ghetti B, Spillantini MG, Goedert M (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22:9340–9351PubMedGoogle Scholar
  3. 3.
    Anderson JM, Hampton DW, Patani R, Pryce G, Crowther RA, Reynolds R, Franklin RJ, Giovannoni G, Compston DA, Baker D, Spillantini MG, Chandran S (2008) Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. Brain 131:1736–1748. doi:10.1093/brain/awn119 PubMedCrossRefGoogle Scholar
  4. 4.
    Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van der Zee EA, Harkany T, Holzer M, Hartig W (2003) Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 23:6972–6981PubMedGoogle Scholar
  5. 5.
    Augustinack JC, Schneider A, Mandelkow EM, Hyman BT (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103:26–35. doi:10.1007/s004010100423 PubMedCrossRefGoogle Scholar
  6. 6.
    Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672. doi:10.1038/nrn2194 PubMedCrossRefGoogle Scholar
  7. 7.
    Bandyopadhyay B, Li G, Yin H, Kuret J (2007) Tau aggregation and toxicity in a cell culture model of tauopathy. J Biol Chem 282:16454–16464. doi:10.1074/jbc.M700192200 PubMedCrossRefGoogle Scholar
  8. 8.
    Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468. doi:10.1002/ana.20016 PubMedCrossRefGoogle Scholar
  9. 9.
    Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123(Pt 6):1174–1183. doi:10.1093/brain/123.6.1174 PubMedCrossRefGoogle Scholar
  10. 10.
    Davie CA, Barker GJ, Webb S, Tofts PS, Thompson AJ, Harding AE, McDonald WI, Miller DH (1995) Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 118(Pt 6):1583–1592. doi:10.1093/brain/118.6.1583 PubMedCrossRefGoogle Scholar
  11. 11.
    De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121(Pt 8):1469–1477. doi:10.1093/brain/121.8.1469 PubMedCrossRefGoogle Scholar
  12. 12.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3):393–399. doi:10.1093/brain/120.3.393 PubMedCrossRefGoogle Scholar
  13. 13.
    Forman MS, Zhukareva V, Bergeron C, Chin SS, Grossman M, Clark C, Lee VM, Trojanowski JQ (2002) Signature tau neuropathology in gray and white matter of corticobasal degeneration. Am J Pathol 160:2045–2053PubMedGoogle Scholar
  14. 14.
    Gasparini L, Terni B, Spillantini MG (2007) Frontotemporal dementia with tau pathology. Neurodegener Dis 4:236–253. doi:10.1159/000101848 PubMedCrossRefGoogle Scholar
  15. 15.
    Goedert M (2004) Tau protein and neurodegeneration. Semin Cell Dev Biol 15:45–49. doi:10.1016/j.semcdb.2003.12.015 PubMedCrossRefGoogle Scholar
  16. 16.
    Goedert M, Jakes R, Crowther RA, Cohen P, Vanmechelen E, Vandermeeren M, Cras P (1994) Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer’s disease: identification of phosphorylation sites in tau protein. Biochem J 301(Pt 3):871–877PubMedGoogle Scholar
  17. 17.
    Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168. doi:10.1016/0896-6273(92)90117-V PubMedCrossRefGoogle Scholar
  18. 18.
    Hampton DW, Anderson J, Pryce G, Irvine KA, Giovannoni G, Fawcett JW, Compston A, Franklin RJ, Baker D, Chandran S (2008) An experimental model of secondary progressive multiple sclerosis that shows regional variation in gliosis, remyelination, axonal and neuronal loss. J Neuroimmunol 201–202:200–211. doi:10.1016/j.jneuroim.2008.05.034 PubMedCrossRefGoogle Scholar
  19. 19.
    Kitazawa M, Trinh DN, Laferla FM (2008) Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3beta. Ann Neurol 64:15–24. doi:10.1002/ana.21325 PubMedCrossRefGoogle Scholar
  20. 20.
    Luna-Munoz J, Chavez-Macias L, Garcia-Sierra F, Mena R (2007) Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease. J Alzheimers Dis 12:365–375PubMedGoogle Scholar
  21. 21.
    Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Goedert M, Amos LA, Spillantini MG (2007) Interaction of tau protein with the dynactin complex. EMBO J 26:4546–4554. doi:10.1038/sj.emboj.7601878 PubMedCrossRefGoogle Scholar
  22. 22.
    Mott RT, Dickson DW, Trojanowski JQ, Zhukareva V, Lee VM, Forman M, Van Deerlin V, Ervin JF, Wang DS, Schmechel DE, Hulette CM (2005) Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J Neuropathol Exp Neurol 64:420–428PubMedGoogle Scholar
  23. 23.
    Okawa Y, Ishiguro K, Fujita SC (2003) Stress-induced hyperphosphorylation of tau in the mouse brain. FEBS Lett 535:183–189. doi:10.1016/S0014-5793(02)03883-8 PubMedCrossRefGoogle Scholar
  24. 24.
    Schneider A, Araujo GW, Trajkovic K, Herrmann MM, Merkler D, Mandelkow EM, Weissert R, Simons M (2004) Hyperphosphorylation and aggregation of tau in experimental autoimmune encephalomyelitis. J Biol Chem 279:55833–55839. doi:10.1074/jbc.M409954200 PubMedCrossRefGoogle Scholar
  25. 25.
    Shriver LP, Dittel BN (2006) T-cell-mediated disruption of the neuronal microtubule network: correlation with early reversible axonal dysfunction in acute experimental autoimmune encephalomyelitis. Am J Pathol 169:999–1011. doi:10.2353/ajpath.2006.050791 PubMedCrossRefGoogle Scholar
  26. 26.
    Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288. doi:10.1126/science.1105681 PubMedCrossRefGoogle Scholar
  27. 27.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285. doi:10.1056/NEJM199801293380502 PubMedCrossRefGoogle Scholar
  28. 28.
    Wegner C, Esiri MM, Chance SA, Palace J, Matthews PM (2006) Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 67:960–967. doi:10.1212/01.wnl.0000237551.26858.39 PubMedCrossRefGoogle Scholar
  29. 29.
    Zhukareva V, Shah K, Uryu K, Braak H, Del Tredici K, Sundarraj S, Clark C, Trojanowski JQ, Lee VM (2002) Biochemical analysis of tau proteins in argyrophilic grain disease, Alzheimer’s disease, and Pick’s disease: a comparative study. Am J Pathol 161:1135–1141PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Jane Marian Anderson
    • 1
  • Rickie Patani
    • 1
  • Richard Reynolds
    • 2
  • Richard Nicholas
    • 2
  • Alastair Compston
    • 1
  • Maria Grazia Spillantini
    • 1
  • Siddharthan Chandran
    • 1
  1. 1.Cambridge Centre for Brain Repair, Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
  2. 2.Department of Cellular and Molecular NeuroscienceImperial College Faculty of Medicine, Charing Cross Hospital CampusLondonUK

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