Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer disease is characterized by neurofibrillary pathology containing paired helical filaments (PHF). These abnormal filaments consist of a modified form of microtubule associated protein tau. The modification involves phosphorylation. In this mini review, we summarize recent studies regarding the differences between normal tau and PHF-tau, focusing especially on the extent and the site of phosphorylation. We also discuss the mechanisms possible involved in the development of PHF.
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PMID:Neurofibrillary degeneration and microtubule associated protein tau. 130 32

Seventy-one tumors of the central nervous system in children were studied immunohistologically. Thirty-seven were classified histologically as PNETs, of which 35 were located in the cerebellum (medulloblastomas), one in the cerebrum, and one in the spinal cord. The 34 non-PNETs included five ependymomas, seven gangliogliomas, 15 astrocytomas, and seven tumors of other histology. We used monoclonal antibodies specific for neurofilament (NF) triplet proteins, for microtubule associated protein 2 and tau protein and for glial fibrillary acidic protein (GFAP) and myelin basic protein. In addition, a monoclonal antibody to epithelial membrane antigen was applied. The presence or absence of these antigens defined four major groups of PNETs: 1) PNETs not otherwise specified (10 cases), 2) PNETs with neuronal differentiation (eight cases), 3) PNETs with astrocytic differentiation (six cases), and 4) PNETs with both neuronal and astrocytic differentiation (12 cases). One case showed ependymal differentiation. The pattern of expression of NF isoforms in PNETs was reminiscent of that seen during normal mammalian development, such that phosphorylated NF-H was only present in combination with NF-M and NF-L. Among the other central nervous system tumors, all astrocytomas and gangliogliomas were positive for GFAP, and the gangliogliomas also expressed all NF isoforms. Three atypical teratoid tumors and two rhabdoid tumors showed strong positivity for epithelial membrane antigen and also for GFAP. We conclude that the differentiation antigens described here serve to distinguish PNETs from other pediatric central nervous system tumors and to identify subsets of PNETs. Accordingly, PNETs represent a heterogeneous group of pediatric brain tumors capable of neuronal and glial differentiation.
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PMID:Molecular markers of primitive neuroectodermal tumors and other pediatric central nervous system tumors. Monoclonal antibodies to neuronal and glial antigens distinguish subsets of primitive neuroectodermal tumors. 255 87

Neurofibrillary lesions found in Alzheimer disease (AD) are known to react with antibodies raised against different molecules. At least 20 components have been detected in neurofibrillary tangles. These components can be roughly categorized into five groups, which include structural proteins, kinases and other cytosolic enzymes, stress-related molecules, amyloid and amyloid binding proteins, and others. Among them, an abnormal form of microtubule associated protein tau, PHF-tau, is a major component of Alzheimer NFT. Kinases associated with NFT, especially those belonging to the family of proline-directed Ser/Thr kinases, are considered to be important for PHF-tau hyperphosphorylation. A potentially significant kinase is a Cdc2-related kinase, which is associated tightly with paired helical filaments, has a molecular weight of 33kDa and is different from other known Cdc2-related kinases. The possibility that some of the NFT-associated elements may play an active role in the pathogenesis of Alzheimer's disease was supported by recent studies, in which advanced glycated products and markers of oxidant stress were located in NFT. In addition, PHF-tau was found to be glycated, and in vitro glycated tau was capable of inducing oxidant stress. Further characterization of different components of NFT by biochemical and other approaches will be important for understanding the mechanisms involved in the supramolecular aggregation of PHF within NFT.
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PMID:Alzheimer neurofibrillary lesions: molecular nature and potential roles of different components. 756 47

Recently, a mitogen activated protein kinase has been implicated in the generation of a phosphorylated paired helical filament (PHF) epitope recognized by the monoclonal antibody AT8. This epitope consists of phosphorylated serines 199 and/or 202 of the human microtubule associated protein tau. Theoretically, aside from abnormal kinase activity, inhibition of phosphatase activity could also be involved in the abnormal phosphorylation status of the microtubule associated protein tau. To investigate this, we incubated LA-N-5 neuroblastoma cells with okadaic acid, a specific inhibitor of phosphatase 2A. We found that incubating neuroblastoma cells with okadaic acid induces the abnormally phosphorylated AT8 epitope. The effect of okadaic acid is time and dose dependent and is reversible. Our findings suggest that phosphatase activity is important in the regulation of the phosphorylation state of tau. Phosphatases may act directly on tau or may influence the activity of mitogen activated protein kinase. Incubation of LA-N-5 neuroblastoma cells with okadaic acid provides a cellular model in which the generation of a well-defined PHF-tau epitope can be investigated.
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PMID:The phosphatase inhibitor okadaic acid induces a phosphorylated paired helical filament tau epitope in human LA-N-5 neuroblastoma cells. 768 10

Paired helical filaments (PHF) characteristic of Alzheimer neurofibrillary lesions are known to contain a modified form of microtubule associated protein tau. These proteins, PHF-tau, differ from normal tau in the extent and the site of phosphorylation. To determine whether PHF-tau, tau proteins from normal adult brains (N-tau), tau proteins from Alzheimer brains not associated with PHF (A-tau), and tau proteins from fetal brains (F-tau) differ in racemization, these proteins were compared for their D-aspartate content. The results demonstrated that PHF-tau contain more D-aspartate than N-tau, A-tau and F-tau. The average percentage D-aspartate for these proteins, after a correction for background, are 4.9%, 2.8%, 1.6%, and 1% for PHF-tau, N-tau, A-tau and F-tau, respectively. It remains to be determined if the increase in D-aspartate is a consequence of PHF formation. It is also unknown if the change in D-aspartate content in PHF-tau is associated with phosphorylation, which alters the susceptibility of tau to proteolysis.
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PMID:Detection of D-aspartate in tau proteins associated with Alzheimer paired helical filaments. 779 27

Molecular analysis of histological hallmarks (neurofibrillary tangles, neuritic plaques, neuropil threads and dystrophic neurites) of Alzheimer diseased brain tissues showed that these lesions contain paired helical filaments. Their major constituent is microtubule associated protein tau that is in an abnormally hyperphosphorylated and truncated state. These diseased forms of tau protein are unable to promote full microtubule assembly. Understanding of the molecular basis of the processes leading to the modifications of tau proteins and paired helical filament formation will form a firm step toward rational drug development and the cure of the Alzheimer's disease.
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PMID:Truncated tau protein as a new marker for Alzheimer's disease. 781

In a normal mature neuron, microtubule associated protein tau promotes the assembly of tubulin into microtubules and maintains the structure of microtubules. In Alzheimer disease brain, tau is abnormally hyperphosphorylated and is the major protein subunit of paired helical filaments (PHF). In the present study, the biological activity of tau in PHF and the effect of dephosphorylation on this activity were examined. PHF were isolated from Alzheimer disease brains and tau from the untreated or alkaline phosphatase-treated PHF was extracted by ultrasonication in microtubule assembly buffer. Tubulin was isolated by phosphocellulose chromatography of three cycled microtubules from bovine brain. PHF-tau did not promote assembly of bovine tubulin into microtubules whereas tau from the dephosphorylated PHF produced a robust microtubule assembly. These studies suggest (i) that in Alzheimer disease tau in PHF is functionally inactive because of abnormal phosphorylation and (ii) that the abnormally phosphorylated site(s) in PHF that inactivates PHF-tau is accessible to enzymatic dephosphorylation in vitro.
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PMID:Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. 804 85

Observations from ultrastructural and immunohistochemical studies suggest that spongiform lesions in the gerbil cochlear nucleus are derived principally from dendrites. Almost one-fifth of the lesion profiles examined ultrastructurally exhibited synaptic contacts with axon terminals. In addition, approximately 80% of lesions are immunopositive for the dendrite-specific microtubule associated protein, MAP2. Ultrastructural studies showed a small percentage (8%) of lesions were derived from myelinated axons, although none were immunohistochemically labelled with antibodies to the tau protein. Staining with the astrocyte-specific markers GFAP, S-100 and vimentin yielded equivocal results, but did not support a major role for astrocytes in lesion formation. The histological profile matches that seen in some other well characterized types of spongiform degeneration.
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PMID:Spongiform degeneration of the gerbil cochlear nucleus: an ultrastructural and immunohistochemical evaluation. 935 48

The microtubule associated protein tau is the main structural component of paired helical filaments (PHFs), aberrant polymers found intracellularly in neurons of brains with the Alzheimer's disease. Glycation is one of the posttranslational modifications that has been found in tau from PHFs, but not in normal brain tau. Studies were carried out with purified tau protein subjected to chemical modifications, in order to further investigate the mechanisms of tau self-association into PHFs. Tau was subjected to modifications affecting reactive lysyl residues, e.g., carbamoylation with potassium cyanate and glycation reaction with glucose. The effects of these modifications to produce functional alterations in tau capacity to bind brain tubulin and to induce microtubule assembly were investigated. Chemically-modified tau and tau of Alzheimer's type exhibited a similar microtubule interaction behavior as analysed by overlay assays, but those were different than normal tau controls. On the other hand, studies of the microtubule assembly kinetics indicated that the reported tau modifications resulted in a loss of its capacity to promote microtubule assembly from purified tubulin preparations. The data on the differences in the electrophoretic profiles, Western blots and the overlay patterns, along with those on the microtubule polymerisation of normal brain tau as compared with both modified and Alzheimer's tau, suggest changes in the functional behavior of this protein as a result of its structural modifications. These studies were complemented with an immunogold analysis at the electron microscope level, which indicated that the modified tau did not incorporate into assembled microtubules. These findings, combined with the results on tau chemical modifications suggest that the reactive lysine residues within functional domains on tau, e.g., those of the repetitive binding motifs, were affected by these modifications. Furthermore, these observations provide new clues to understand the anomalous interactions of tau in Alzheimer's disease.
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PMID:Modification of tau to an Alzheimer's type protein interferes with its interaction with microtubules. 984 94

Hyperphosphorylated microtubule associated protein tau, present in neurofibrillary tangles, is a prominent pathological feature of Alzheimer's disease (AD). The gene encoding tau (MAPT) was recently found mutated in frontotemporal dementia (FTD) and other tauopathies. We studied MAPT as a candidate gene in the etiology of AD. The study population consisted of 101 early-onset AD patients and 117 controls. Mutation analysis did not detect causal mutations in exons 9 to 13 encoding the microtubule-binding domains involved in FTD, however, two novel polymorphisms were detected in exon 9. Using the Ala169 polymorphism in exon 9 and a previously reported (CA)n-repeat polymorphism in intron 9, an association study was performed. No association with early-onset AD was detected. Together, our data indicate that MAPT does not play a role in early-onset AD.
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PMID:Mutation screening of the tau gene in patients with early-onset Alzheimer's disease. 1062 29


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