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Abnormal tau phosphorylation in primary progressive multiple sclerosis

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Abstract

Although neurodegeneration is the pathological substrate of progression in multiple sclerosis (MS), the underlying mechanisms remain unresolved. Abnormal phosphorylation of tau, implicated in the aetiopathogenesis of a number of classic neurodegenerative disorders, has also recently been described in secondary progressive MS (SPMS). In contrast to SPMS, primary progressive MS (PPMS) represents a significant subset of patients with accumulating neurological disability from onset. The neuropathological relationship between SPMS and PPMS is unknown. Against this background, we investigated tau phosphorylation status in five cases of PPMS using immunohistochemical and biochemical methods. We report widespread abnormal tau hyperphosphorylation of the classic tau phospho-epitopes occurring in multiple cell types but with a clear immunohistochemical glial bias. In addition, biochemical analysis revealed abnormally phosphorylated insoluble tau in all cases. These findings establish a platform for further study of the role of insoluble tau formation, including determining the relevance of glial tau pathology, in the neurodegenerative phase of MS.

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Abbreviations

CNS:

Central nervous system

LFB:

Luxol fast blue

mAb:

Monoclonal antibody

NGS:

Normal goat serum

NAWM:

Normal appearing white matter

PB:

Phosphate buffer

PBS:

Phosphate buffered saline

Triton/PBS:

Triton/phosphate buffered saline

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Acknowledgments

These studies were supported by the Webb Trust Fund, Husky Foundation, Sir David Walker Trust Fund, Medical Research Council, Wellcome Trust, National Institute for Health Research (NIHR), MS Society of Great Britain and Northern Ireland, and the National Multiple Sclerosis Society, USA. Tissue samples were supplied by the UK MS Tissue Bank, funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland, registered charity 207495. The authors report no other disclosures.

Conflict of interest statement

We declare no known conflict of interest.

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Authors and Affiliations

  1. Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, UK

    Jane Marian Anderson, Rickie Patani, Alastair Compston, Maria Grazia Spillantini & Siddharthan Chandran

  2. Department of Cellular and Molecular Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, UK

    Richard Reynolds & Richard Nicholas

  3. Centre for Multiple Sclerosis Research, University of Edinburgh, Edinburgh, UK

    Siddharthan Chandran

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  1. Jane Marian Anderson
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  2. Rickie Patani
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  3. Richard Reynolds
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  5. Alastair Compston
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  6. Maria Grazia Spillantini
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Correspondence to Siddharthan Chandran.

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J. M. Anderson and R. Patani are co-first authors.

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Anderson, J.M., Patani, R., Reynolds, R. et al. Abnormal tau phosphorylation in primary progressive multiple sclerosis. Acta Neuropathol 119, 591–600 (2010). https://doi.org/10.1007/s00401-010-0671-4

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