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Brain Advance Access originally published online on June 21, 2008
Brain 2008 131(7):1736-1748; doi:10.1093/brain/awn119
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis

J. M. Anderson1, D. W. Hampton1, R. Patani1, G. Pryce2, R. A. Crowther3, R. Reynolds4, R. J. M. Franklin1,5, G. Giovannoni2, D. A. S. Compston1, D. Baker2, M. G. Spillantini1 and S. Chandran1

1Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, 2Neuroimmunology Unit, Neuroscience Centre, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, 3Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge, 4Department of Cellular and Molecular Neuroscience, Imperial College Faculty of Medicine, Charing Cross Hospital Campus, Fulham Palace Road, London and 5Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK

Correspondence to: Siddharthan Chandran, Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, UK E-mail: sc222{at}cam.ac.uk

The pathological correlate of clinical disability and progression in multiple sclerosis is neuronal and axonal loss; however, the underlying mechanisms are unknown. Abnormal phosphorylation of tau is a common feature of some neurodegenerative disorders, such as Alzheimer's disease. We investigated the presence of tau hyperphosphorylation and its relationship with neuronal and axonal loss in chronic experimental autoimmune encephalomyelitis (CEAE) and in brain samples from patients with secondary progressive multiple sclerosis. We report the novel finding of abnormal tau phosphorylation in CEAE. We further show that accumulation of insoluble tau is associated with both neuronal and axonal loss that correlates with progression from relapsing–remitting to chronic stages of EAE. Significantly, analysis of secondary progressive multiple sclerosis brain tissue also revealed abnormally phosphorylated tau and the formation of insoluble tau. Together, these observations provide the first evidence implicating abnormal tau in the neurodegenerative phase of tissue injury in experimental and human demyelinating disease.

Key Words: tau; secondary progressive multiple sclerosis; experimental autoimmune encephalomyelitis; axonopathy; neuronal loss

Abbreviations: CEAE, chronic experimental autoimmune encephalomyelitis; CREAE, chronic relapsing experimental autoimmune encephalomyelitis; LFB, Luxol fast blue; mAb, monoclonal antibody; NGS, normal goat serum; PB, phosphate buffer; PBS, phosphate buffered saline; RM2EAE, second remission experimental autoimmune encephalomyelitis; TX-PBS, Triton-phosphate buffered saline

Received February 5, 2008. Revised April 29, 2008. Accepted May 12, 2008.


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