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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conflicting evidence supports a role for tau as an essential neuronal cytoskeletal protein or as a redundant protein whose function can be fulfilled by other microtubule-associated proteins. To investigate the function of tau in axonogenesis, we created tau deficient mice by disrupting the TAU gene. The engineered mice do not express the tau protein, appear physically normal and are able to reproduce. In contrast to a previously reported tau knockout mouse, embryonic hippocampal cultures from tau deficient mice show a significant delay in maturation as measured by axonal and neuritic extensions. The classic technique of selectively enhancing axonal growth by growth on laminin substrates failed to restore normal neuronal maturation of tau knockout neurons. By mating human TAU-gene transgenic and tau knockout mice, we reconstituted tau-deficient neurons with human tau proteins and restored a normal pattern of axonal growth and neuronal maturation. The ability of human tau proteins to rescue tau-deficient mouse neurons confirms that tau expression affects the rate of neurite extension.
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PMID:Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. 1122 61

Axonal signals activate myelinogenesis via regulation of the extent to which oligodendrocyte (OLG) processes wrap around the axon. The cytoskeleton in OLG processes is actively involved in myelination and is a putative target for axonal regulation of myelination. The axon-associated neuregulins may regulate the cytoskeleton extensions in OLG processes. Here, we report that the neuregulin neu differentiation factor (NDF) increases the expression of tau mRNA and tau protein in OLGs. Treatment of neonatal OLGs with alpha-NDF or beta-NDF resulted in dramatic increases in the length of OLG processes, which appeared either as singular unbranched extensions or as a network of extensively branched processes. By immunoblot analysis with tau-1 mAb, which recognizes the dephosphorylated form of the tau proteins, neonatal OLGs treated with alpha-NDF or beta-NDF, had an increase in tau protein levels. The increase of tau levels in beta-NDF-treated cells is much greater than the twofold increase present in alpha-NDF-treated cells. By immunoblot analysis with the phosphorylation-insensitive tau-5 mAb, beta-NDF-treated cells had a twofold increase in tau. Immunoblot analysis suggest that alpha-NDF and beta-NDF promote a twofold increase in the tau protein levels in OLG, with the beta-factor also promoting a tau dephosphorylation. Using promoters spanning the amino-terminal region of tau, we found that OLGs treated with alpha-NDF or beta-NDF contained approximately twofold more tau mRNA than untreated cells. However, there was no qualitative difference between control and NDF-treated cells in the pattern of tau mRNA isoforms expressed. A model is proposed in which the axonal NDF-induced regulation of tau expression in OLGs may be part of the mechanism by which the axon regulates myelination.
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PMID:Neu differentiation factor regulates tau protein and mRNA in cultured neonatal oligodendrocytes. 1146 Feb 70

Cerebral dysfunction without corresponding structural pathology has been reported in brain imaging studies of violent offenders. Biochemical markers in the CSF reflect various types of CNS pathology, such as blood-brain barrier dysfunction (CSF/S albumin ratio), infectious or inflammatory processes (IgG and IgM indices), neuronal or axonal degeneration (CSF-tau protein) and synaptic de- or regeneration (CSF-growth associated protein-43 (GAP-43)). We compared these CSF markers in 19 non-psychotic perpetrators of severe violent crimes undergoing pretrial forensic psychiatric investigation and 19 age- and sex-matched controls. Index subjects had significantly higher albumin ratios (p = 0.002), indicating abnormal vascular permeability as part of the complex CNS dysfunction previously reported in violent offenders. Axis I disorders, including substance abuse or current medication, did not explain this finding. Since Ig-indices, CSF-tau protein or CSF-GAP-43 were not increased, there was no support for inflammation or neuronal/synaptic degeneration as etiological factors to CNS dysfunction in this category of subjects.
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PMID:CSF studies in violent offenders. II. Blood-brain barrier dysfunction without concurrent inflammation or structure degeneration. 1151 53

Subcellular mRNA localization, a fundamental mechanism for regulating gene expression, leads to local protein translation that results in the generation of neuronal cell polarity. In this study, we have used P19 embryonic carcinoma cells, which are amenable to transfection, and selection of clonal stable cell lines that are not overexpressing the constructs. We identified the 3' untranslated region (3'UTR) tau axonal localization signal and examined its effect on tau protein localization in nondifferentiated and neuronally differentiated P19 cells. Using GFP-tagged tau constructs combined with in situ hybridization analysis, we demonstrated colocalization of the targeted tau mRNA and its translated protein in the axon and growth cone. Absence of or mutation in the 3'UTR axonal targeting region of tau mRNA resulted in suppression of tau mRNA localization, and both tau mRNA and tau protein remained in the cell body. Swapping between the 3'UTR tau mRNA axonal localization signal and the 3'UTR MAP2 mRNA dendritic targeting signal proved that the localization of the proteins into the axon or dendrites depends on the specific 3'UTR targeting signals. Moreover, the identification of ribosomal proteins in the axon lends further support to the presence of protein synthetic machinery in the axons, a prerequisite for local translation. It is suggested therefore that the P19 cell system can be used to analyze mutations that affect mRNA transport and local translation and that it has the potential of being used to examine the onset of the neuronal differentiation process.
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PMID:Axonal tau mRNA localization coincides with tau protein in living neuronal cells and depends on axonal targeting signal. 1151 47

Oligodendrocytes elaborate an extensive network of multibranched processes and flat membranous sheets. Microtubules (MT) participate in the elaboration and stabilization of myelin-forming processes and are essential for cellular sorting processes. Microtubule-associated proteins (MAPs) are involved in the regulation and stabilization of the dynamic MT network. It has been shown previously that oligodendrocytes express the MAP tau, a phosphoprotein most abundant in neurons of the CNS. In this article, we demonstrate for the first time that oligodendrocytes contain all six tau isoforms, and that tau mRNA and protein expression is developmentally regulated. Immunoblot analysis reveals that tau protein is more abundant, and mature isoforms are more prominent at later stages of development. During the first week of culture maturation, a marked decrease in phosphorylation is observable. Using an RT-PCR approach, we can show that oligodendrocytes express small amounts of exon 3 containing isoforms and that during culture maturation, tau mRNA splice products with 3 MT-binding domains (3R) decrease and mRNA with 4 MT-binding domains (4R) increase. In situ hybridization study demonstrates that tau mRNA is present in precursor cells and in mature oligodendrocytes. Tau mRNA is actively transported into the cellular processes, is specifically present in the primary and some of the secondary processes, enriched at the turning and branching points and the growing tips, and often appears as small patches. Hence, localized tau translation at specific sites in the cellular extensions might contribute to the regulation of MT stability during process formation, early axonal contact establishment, and myelination.
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PMID:Developmental changes of tau protein and mRNA in cultured rat brain oligodendrocytes. 1157 87

The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss. Interaction of tau with microtubules is thought to be regulated by phosphorylation. Investigating FTDP-17 mutations transiently expressed as enhanced green fluorescent protein (EGFP)-tagged proteins for the first time in differentiated neuronal cells, we found that two out of three missense mutations showed surprisingly decreased phosphorylation at the pathologically relevant S202/T205 site, mutant EGFP-tau being completely dephosphorylated in most cells. Moreover, phosphorylation at the S396/S404 site was moderately decreased for all mutant isoforms. Although microtubule integrity was not affected, with all mutants tested we demonstrated an increase in cellular tau protein level, some of which is microtubule-bound. Further enhancing this EGFP-tau accumulation by inhibition of tau degradation resulted in the previously less phosphorylated mutant EGFP-tau becoming highly phosphorylated. We conclude that the missense tau mutations primarily result in an excess of neuronal tau, which may interfere with important cellular functions such as axonal transport.
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PMID:Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells. 1173 5

Biochemical markers of brain damage, e.g. ischemic stroke, should reflect the volume of irreversibly damaged brain parenchyma and the clinical outcome in a single patient in order to allow estimation of prognosis at an early stage. Tau protein, which derives predominantly from neurons and axons, is elevated in the cerebrospinal fluid of patients with neurodegenerative disease. This makes tau protein a potential marker of neuronal/axonal injury. In order to test this hypothesis, the current study aimed at showing that tau protein is measurable in the blood after acute ischemic stroke and that it correlates with clinical disability and stroke volume. In a longitudinal prospective study we measured tau protein serum levels with an ELISA in 30 patients longitudinally after ischemic stroke. Tau protein was detectable within 5 days after ischemia in the sera of 7/20 patients with MRI-proven infarction and in 2/10 patients with transitory ischemic attack; both of them had a small infarction visible on the MRI scan. Tau protein was measurable within 6 h after symptom onset, peaked after 3-5 days and correlated with infarct volume and disability after 3 months. In conclusion, serum tau protein is a candidate marker of axonal injury. In stroke, its clinical use is limited, because it is detectable only in a proportion of patients.
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PMID:Serum tau protein level as a marker of axonal damage in acute ischemic stroke. 1180 92

The neuronal microtubule-associated protein tau promotes microtubule assembly and has been implicated in the development of axonal morphology. In this study, PC12 cells were transiently transfected with constructs coding fusion proteins of human tau with green fluorescent protein (GFP). Expression of tau constructs actively stabilized microtubules. Expression of the C-terminus of tau can mimic this effect in living cells, though to a lesser extent because of the absence of the tau N-terminus. However, tau colocalization with microtubules did not require the presence of the tau N-terminus. Transient expression of tau (including tau24, a four-repeat human tau isoform encoded in 383 residues, and tau23, human fetal tau isoform encoded in 352 residues) stimulated process formation in PC12 cells, and this occurred faster with tau24 than with tau23. The residues (residues 154-172 in tau23) that confer microtubule nucleation activity of tau in vitro are not required for tau-directed process formation. However, when tau induces the formation of cellular processes in response to cortical breakdown by cytochalasin B, residues 154-172 must be present. Thus, it appears that tau may serve to promote cellular process outgrowth in cultured neuronal cells and that C-terminus of tau is essential to this process.
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PMID:Transient expression of fluorescent tau proteins promotes process formation in PC12 cells: contributions of the tau C-terminus to this process. 1189 75

Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles.
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PMID:Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice. 1193 41

The examination of biochemical markers of the damage of the central nervous system may be the excellent complement of the neuroimaging methods. There are factors in the cerebrospinal fluid which indicate the damage of the precise structures of the CNS. In this paper there are described the main markers which are used in diagnostic multiple sclerosis: myelin basic protein (MBP) as a marker of demyelination of the white matter, neuron specific enolase (NSE) as a marker of neuronal damage, tau protein, 14-3-3 protein, neurofilament protein-subunit light (NFL) as markers of axonal damage and S-100 protein and glial fibrillary acidic protein as markers of astroglial damage.
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PMID:Biochemical markers of damage of the central nervous system in multiple sclerosis. 1197 45


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