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

Anderson, Jane; Hampton, David W.; Patani, Rickie; Pryce, Gareth; Crowther, R. Anthony; Reynolds, Rebecca; Franklin, Robin J.M.; Giovannoni, Gavin; Compston, D. A. S.; Baker, David; Spillantini, M. G.; Chandran, Siddharthan

doi:10.1093/brain/awn119

Cited by 122 publications

(96 citation statements)

References 56 publications

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“…GSK3b encodes for a serine threonine kinase that phosphorylates a variety of nuclear and cytoplasmic proteins, including tau. Abnormally phosphorylated tau and insoluble tau were found in progressive MS (Anderson et al, 2008(Anderson et al, , 2010. To investigate whether GSK3b is associated with MS, SNPs in GSK3b were genotyped in an Italian casecontrol dataset (Galimberti et al, 2011).…”

Section: Glycogen Synthase Kinase 3 Beta (Gsk3b) and Taumentioning

confidence: 99%

Genetics of primary progressive multiple sclerosis

Cree

2014

Handbook of Clinical Neurology

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Section: Glycogen Synthase Kinase 3 Beta (Gsk3b) and Taumentioning

confidence: 99%

Genetics of primary progressive multiple sclerosis

Cree

2014

Handbook of Clinical Neurology

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“…Injured axons in MS lesions accumulate amyloid precursor protein (APP), which is detectable only in axons with impaired fast axonal transport (Ferguson et al, 1997; Sherriff et al, 1994). The impairment of axonal transport may result from the recently demonstrated presence in MS lesions of hyperphosphorylated tau (Anderson et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In addition hyperphosphorylated insoluble tau has been observed in several cases of primary and secondary progressive MS but not in an example of relapsing remitting MS (Anderson et al, 2008, 2009, 2010). In a mouse model of chronic inflammation‐driven demyelination the levels of insoluble tau positively correlate with axonal loss (Anderson et al, 2008), suggesting that the conversion of soluble to insoluble tau may contribute to axonal pathology in the progressive stage of MS. The phosphorylation status of tau is finely regulated by several kinases and phosphatases (Hanger et al, 2009), and its hyperphosphorylation can be also physiological, for example during fetal brain development, hypothermia, and hibernation (Spillantini and Goedert, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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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 2016;64:457–471

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“…13,18 Most widely used assays for tau are adequate for CSF, but not sensitive enough to reliably detect low concentrations found in blood. 12 Increases of tau were observed in CSF after severe TBI, peaking 1 week after the brain trauma.…”

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confidence: 99%

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

Bogoslovsky

Wilson

Yao

et al. 2017

Journal of Neurotrauma

175

126

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Glial fibrillary acidic protein (GFAP), microtubule-associated protein tau, and amyloid b peptide (Ab42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single molecule array (Simoa) is a novel technology that employs highly sensitive immunoassays for accurate measurements of candidate biomarkers found at low concentration in biological fluids. Our objective was to trace the trajectory of tau, GFAP, and Ab42 levels in plasma from the acute through subacute stages after TBI, compared with controls. Samples from 34 TBI subjects enrolled in the Citicoline Brain Injury Treatment Trial (COBRIT) were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 months after injury. Plasma was collected within 24 h (Day 0), and 30 and 90 days after the TBI. Plasma collected from 69 healthy volunteers was used for comparison. At every time point, increases were noted in plasma GFAP ( p < 0.0001 for all comparisons), tau ( p < 0.0001, p < 0.0001, and p = 0.0044, at Days 0, 30, and 90, respectively), and Ab42 ( p < 0.001, p < 0.0001, and p = 0.0203, respectively) in TBI cases compared with controls. The levels were maximal at Day 0 for GFAP and tau and at Day 30 for Ab42. Area under curve (AUC) analyses for Day 0 GFAP and tau were excellent for discrimination of complicated mild TBI (cmTBI) from controls (0.936 and 0.901, correspondingly). Discriminant component analysis (DCA) for all three biomarkers at Days 0 and 30 differentiated controls from cmTBI (91.1% and 89.7% correctly classified, at each time point). Duration of post-traumatic amnesia (PTA) correlated weakly with tau levels at 30 days (Spearman's r = 0.40; 95% CI 0.0003-0.60, p = 0.044). The Marshall CT Grade on admission correlated weakly with Day 30 tau levels (Spearman's r = 0.41; 95% CI 0.04-0.68, p = 0.027). Day 30 Ab42 correlated with GOSE (standardized b -0.486, p = 0.042). GFAP, tau and Ab42 were increased up to 90 days after TBI compared with controls. Total tau levels correlated with clinical and radiological variables of TBI severity. Plasma Ab42 correlated with clinical outcome. Combination of all three biomarkers at Days 0 and 30 can be used to differentiate controls from cmTBI populations, and may be useful as biomarkers of TBI in both acute and subacute phases.

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

Cited by 122 publications

References 56 publications

Genetics of primary progressive multiple sclerosis

Genetics of primary progressive multiple sclerosis

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

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