Evidence for abnormal tau phosphorylation in early aggressive multiple sclerosis

ArticleinActa Neuropathologica 117(5):583-9 · June 2009with5 Reads
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.
    • "Axonal transport impairment is also present in MS lesions (Ferguson et al., 1997), which may be linked to the presence of tau hyperphosphorylation that we have previously described (Anderson et al., 2008Anderson et al., , 2009Anderson et al., , 2010). In P301S-htau mice the early axonal injury was associated with microgliosis creating an inflammatory environment (Fig. 2). "
    [Show abstract] [Hide abstract] ABSTRACT: Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule-associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau-induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S-htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2-month-old P301S-htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL-1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S-htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S-htau axons to demyelination-induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S-htau mice compared with Wt mice-derived OPCs. Because the OPCs from P301S-htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice-derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2015.
    Full-text · Article · Nov 2015
    • "Other publications, in accordance with our findings, reported no predictive/prognostic value of CSF Tau [6,28]. The rationale for examining p-Tau as a potential marker in MS was based on pathological studies reporting p-Tau accumulation within the brains of progressive MS patients313233. This rationale is further supported by findings demonstrating that p-Tau accumulates within the brainstem of rats with acute experimental autoimmune encephalitis (EAE) [34], and also in the spinal cord of mice in a chronic model, correlating with neurodegeneration [32]. However, to our knowledge, no ELISA studies on CSF p-Tau could detect significant difference between MS and control groups [7,8,10], and also the latest published study (with no control group involved) [30] recorded p-Tau levels in MS within a range matching those seen in control population. "
    [Show abstract] [Hide abstract] ABSTRACT: Biomarkers capable of predicting the clinical course and the rate of disease progression in multiple sclerosis are currently unavailable. Our objective was to examine if the levels of proteins associated with axonal and neuronal degeneration (Tau, p-Tau and β-amyloid1-42) and T-cell-mediated autoimmunity (osteopontin) are altered in the cerebrospinal fluid (CSF) of MS patients, and to assess their potential in reflecting the clinical severity and predicting the progression and clinical evolution of early MS. The CSF samples collected from patients presenting with different clinical forms of MS were evaluated by enzyme-linked immunosorbent assays. The patients were regularly followed-up and their clinical status was re-evaluated 5years after sampling. The results demonstrated that while CSF levels of Tau, p-Tau and β-amyloid1-42 did not differ between MS and Control groups, the levels of osteopontin were significantly elevated in MS patients. This increase was associated with the presence of a relapse and correlated with clinical severity, which findings were independent of age and blood-CSF barrier function. However, none of the examined protein levels differed significantly between groups with different clinical evolutions and no positive correlations with clinical progression could be detected. We conclude that Tau, p-Tau and β-amyloid1-42 are inappropriate as biomarkers in MS. This is the first report on CSF osteopontin as an independent marker of clinical severity in definite MS.
    Full-text · Article · May 2013
    • "These findings reinforce the importance of early intervention to overcome remyelination failure, but also highlight the need to understand the mechanisms underpinning this phenomenon [48]. Detailed pathological analyses of more chronic progressive MS cases have also yielded valuable insights including an association of progressive disease with insoluble tau accumulation [67,68], not seen in early aggressive disease [66]. Further similar studies are necessary not only to refine current lesion taxonomy, but also to deepen our understanding of the cellular and molecular temporal evolution of demyelinating lesions. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Dec 2012
Show more

  • undefined · undefined
  • undefined · undefined
  • undefined · undefined