Evidence for abnormal tau phosphorylation in early aggressive multiple sclerosis

Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, UK.
Acta Neuropathologica (Impact Factor: 10.76). 06/2009; 117(5):583-9. DOI: 10.1007/s00401-009-0515-2
Source: PubMed


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.

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    • "Pathological studies from patients with early and aggressive multiple sclerosis have proven to be a valuable resource for understanding early pathological events [65,66], including those associated with remyelination failure. Neuropathological studies of such (hyper-) acute lesions exhibiting remyelination failure have been associated with the following phenomena: presence of differentiated oligodendrocytes, astrocyte/oligodendrocyte interaction (emperipolesis), malformed (nodular) myelin sheaths, active demyelination of remyelinated lesions (“second hit” lesions). "
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    ABSTRACT: Multiple Sclerosis (MS) is an inflammatory demyelinating neurodegenerative disorder of the brain and spinal cord that causes significant disability in young adults. Although the precise aetiopathogenesis of MS remains unresolved, its pathological hallmarks include inflammation, demyelination, axonal injury (acute and chronic), astrogliosis and variable remyelination. Despite major recent advances in therapeutics for the early stage of the disease there are currently no disease modifying treatments for the progressive stage of disease, whose pathological substrate is axonal degeneration. This represents the great and unmet clinical need in MS. Against this background, human stem cells offer promise both to improve understanding of disease mechanism(s) through in-vitro modeling as well as potentially direct use to supplement and promote remyelination, an endogenous reparative process where entire myelin sheaths are restored to demyelinated axons. Conceptually, stem cells can act directly to myelinate axons or indirectly through different mechanisms to promote endogenous repair; importantly these two mechanisms of action are not mutually exclusive. We propose that discovery of novel methods to invoke or enhance remyelination in MS may be the most effective therapeutic strategy to limit axonal damage and instigate restoration of structure and function in this debilitating condition. Human stem cell derived neurons and glia, including patient specific cells derived through reprogramming, provide an unprecedented experimental system to model MS “in a dish” as well as enable high-throughput drug discovery. Finally, we speculate upon the potential role for stem cell based therapies in MS.
    International Journal of Molecular Sciences 12/2012; 13(11):14470-91. DOI:10.3390/ijms131114470 · 2.86 Impact Factor
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    • "Abnormal phosphorylation of tau can lead to the formation of potentially neurotoxic insoluble tau aggregates that have been shown to be characteristic features of common neurodegenerative diseases [97, 99, 100]. Pathological studies demonstrated the association of abnormally phosphorylated tau (p-tau) protein with SPMS and PPMS [101, 102] but also the absence of insoluble tau fraction in early MS, thus indicating the possibility that insoluble tau accumulates with disease progression [100, 102]. "
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    ABSTRACT: Following emerging evidence that neurodegenerative processes in multiple sclerosis (MS) are present from its early stages, an intensive scientific interest has been directed to biomarkers of neuro-axonal damage in body fluids of MS patients. Recent research has introduced new candidate biomarkers but also elucidated pathogenetic and clinical relevance of the well-known ones. This paper reviews the existing data on blood and cerebrospinal fluid biomarkers of neuroaxonal damage in MS and highlights their relation to clinical parameters, as well as their potential predictive value to estimate future disease course, disability, and treatment response. Strategies for future research in this field are suggested.
    05/2011; 2011(6):767083. DOI:10.1155/2011/767083
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    ABSTRACT: In search of biological marker in multiple sclerosis (MS), total-tau and phospho-tau (Thr181) concentrations were established in CSF and serum of 78 patients with MS, using commercially available kits. Serum and CSF concentrations of IgG, IgM, and albumin were assayed simultaneously to calculate quotients and indices of intrathecal synthesis. Serum t-tau detection was strikingly low (23.1%); therefore, this factor was excluded from further analysis. Serum p-tau levels did not correlate with any of indices or quotients. Unexpectedly, CSF t-tau and p-tau showed an inverse relation with MSSS and EDSS, which has not been published elsewhere. Our results do not support utility of serum t-tau and p-tau as surrogate markers for MS. KeywordsTau protein–Phospho-tau protein–Multiple sclerosis
    Central European Journal of Medicine 04/2011; 6(2):193-200. DOI:10.2478/s11536-011-0003-7 · 0.15 Impact Factor
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