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)

Preparations of dispersed paired helical filaments (PHFs) from the brains of Alzheimer's disease and Down's syndrome patients display on gels three principal bands corresponding to abnormally modified forms of the microtubule-associated protein tau. Interpretation of the pattern is difficult because there are six tau isoforms in normal brain and phosphorylation changes their mobility. By enzymatic dephosphorylation at high temperature, we have shifted the three abnormal bands obtained from dispersed PHFs to align with the six nonphosphorylated tau isoforms. By using antibodies specific for some of the inserts that distinguish the various isoforms and label PHFs, we have established a correspondence between PHFs, abnormal bands, and isoforms. This identification of isoforms is a necessary step in unravelling the molecular pathogenesis of PHFs.
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PMID:Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. 153 Sep 9

Some investigators have described the presence in Alzheimer's disease brain extracts of several abnormal forms of the microtubule-associated protein tau, based on their unusual mobility in SDS/PAGE. It has been proposed that these abnormal forms of tau may be the result of aberrant tau phosphorylation. In this study we show that tau in extracts of Alzheimer's disease brain can be separated into two fractions based upon its solubility (100,000 g x 1 h supernatant) in non-denaturing conditions (100 mM-Mes, pH 6.5, 0.5 mM-MgCl2, 1 mM-EGTA and 1 M-NaCl). The tau isoforms with decreased mobility in SDS/PAGE are predominantly in an insoluble fraction, whereas the soluble tau is indistinguishable by its mobility in SDS/PAGE from tau in soluble extracts of control brain. Insoluble tau displaying abnormal mobility on SDS/PAGE was only found in Alzheimer and adult Down's syndrome brains and was absent from the brains of age-matched controls and from foetal and infant Down's syndrome brains. There was a good correlation between the presence of insoluble tau in brain extracts and the abundance of neurofibrillary tangles and senile neuritic plaques. The monoclonal antibody Tau. 1 stained insoluble tau on Western blots only after treatment of the nitrocellulose transfers with alkaline phosphatase, implying that this insoluble tau is in a particular state of phosphorylation. We conclude that, in Alzheimer's disease, a fraction of tau has a modified phosphorylation state and a decreased solubility; these modifications may precede formation of the neurofibrillary tangles characteristic of Alzheimer's disease and Down's syndrome in adults.
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PMID:Tau in Alzheimer's disease and Down's syndrome is insoluble and abnormally phosphorylated. 182 35

Brains were obtained at autopsy from 24 patients with Down's syndrome, ranging in age from 13 to 71 years. Neurofibrillary tangle containing neurones of the hippocampus were stained using a Palmgren silver method and immunocytochemically (PAP) using antisera to paired helical filament protein, human tau protein and ubiquitin, as primary antibody. Counts of cells stained by each method were compared. In patients under 50 years of age, in whom only a limited number of tangle bearing cells were present, the number of profiles visualized with silver, anti-paired helical filament and anti-tau methods were similar. However, in patients over 50 years of age (and in certain of those under 50), in whom numerous tangles were present, the number of cell profiles visualized with silver and anti-paired helical filament methods were still similar though anti-tau detected fewer positive cells. This was because of the increased presence, in such patients, of extracellular tangles which had "lost" anti-tau immunoreactivity. Such data suggest that although tau protein forms a major antigenic determinant of neurofibrillary tangles in Down's syndrome (as it does in Alzheimer's disease) this protein may only decorate the basic paired helical filament protein skeleton, and is removed by macrophagic activity upon neuronal death. In all patients, anti-ubiquitin revealed fewer tangles than any other method. It is possible that ubiquitin may be present only transiently, within tangles perhaps following initial formation and lasting only as long as the normal protein degradation processes remain viable within the diseased neurone.
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PMID:Immunocytochemical profile of neurofibrillary tangles in Down's syndrome patients of different ages. 255 74

Cell cycle-associated nuclear proteins may have more specialized functions in the adult nervous system in addition to those directly associated with cell proliferation, as suggested by a recent study showing that neurofibrillary tangles (NFT) and dystrophic neurites in Alzheimer's disease (AD) are immunoreactive for the proliferation-associated antigen p105. To further investigate this hypothesis, we studied the expression of another proliferation-associated antigen, Ki-67, in the brains of patients with AD and other neurodegenerative disorders. Formalin-fixed, paraffin-embedded sections from autopsy cases of AD, Down's syndrome with dementia and AD pathology (DS/AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), Lewy body disease (LBD), Parkinson's disease (PD), corticobasal degeneration (CBD), and young and aged normal brains, and from two surgically resected gangliogliomas were immunostained using antibodies to Ki-67 (MIB-1 clone equivalent) and tau (tau). Ki-67 staining was performed following antigen retrieval by microwave heating. Ki-67 labeled NFT that were observed in the AD, DS/AD, PiD, PSP, LBD, and PD cases, one aged normal brain, and one ganglioglioma. Ki-67 generally labeled fewer NFT compared to tau. Pick bodies, ballooned neurons (Pick cells) in CBD and PiD, and nigral corticobasal inclusions in CBD were immunoreactive for tau but not Ki-67. Neither antibody labeled cortical or subcortical Lewy bodies. Our findings suggest that Ki-67 may be involved in the pathogenesis of neurofibrillary degeneration in AD, other neurodegenerative disorders, normal aging, and neoplasms such as ganglioglioma. We postulate a possible role for Ki-67 in the production of the abnormally phosphorylated tau protein that leads to the formation of paired helical filaments within susceptible neurons.
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PMID:Ki-67 immunoreactivity in Alzheimer's disease and other neurodegenerative disorders. 774 28

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these neurodegenerative disorders affected neurons either take up or synthesize lactotransferrin to an abnormally elevated rate. An excessive accumulation of lactotransferrin, as well as transported iron and aluminum, may lead to a cytotoxic effect resulting in the formation of intracellular lesions and neuronal death.
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PMID:The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis. 795 73

Using immunohistochemistry, we examined the localization of four types of proline-directed kinases in the brains of control rats and in the brains of non-demented aged human subjects, subjects with Alzheimer's disease and those with Down's syndrome. The four kinases were: cyclin-dependent kinase (cdk) 5, a component of tau protein kinase (TPK) II; TPK I/glycogen synthase kinase (GSK)-3 beta; GSK-3 alpha; and mitogen-activated protein kinase (MAPK/ERK2). Each of these kinases has been reported to promote the hyperphosphorylation of tau protein in vitro. The kinases were located essentially in neurons, although the intensity and distribution of labeling varied. Antiserum for cdk5 showed the most preferential and consistent labeling of intraneuronal neurofibrillary tangles (NFT). Antiserum for TPK I/GSK-3 beta also labeled intraneuronal NFT. Double immunolabeling for TPK I/GSK-3 beta and tau 1 showed that TPK I/GSK-3 beta was closely associated with NFT. Antiserum for GSK-3 alpha labeled neurons weakly, and the intensity of labeling did not differ between neurons with and without NFT. Antiserum for MAPK labeled neurons in superficial cortical layers, but NFT appeared in both superficial and deep cortical layers. These findings suggest that cdk5 and TPK I/GSK-3 beta are the critically important kinases for the generation in vivo of hyperphosphorylated tau, the main component of the paired helical filaments in NFT.
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PMID:Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. 887 Aug 24

A 53-year-old Japanese woman with a point mutation in mitochondrial DNA (tRNALeu(UUR), nt3243) consistent with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and Alzheimer-type brain pathology is reported. This woman had suffered myopathy and psychosis without any clinical evidence of, stroke-like episodes during the last 10 years of her life, and had died after an accident. At autopsy 30 h post mortem, a part of the brain was snap frozen for biochemical and histochemical studies, and the remaining part was processed for a routine examination and electron microscopy. In the brain there were no ischemic lesions. Instead, primitive/diffuse senile plaques were found throughout the brain, predominantly in the frontal and temporal lobes, while Alzheimer neurofibrillary tangles were found only in the parahippocampal gyrus. These plaques were positive for beta-protein and mostly negative for tau protein, ubiquitin, neurofilaments, alpha-choline acetyltransferase, and acetylcholinesterase. Mutations in codon 331 of the ND2 gene as well as codons 693, 713 and 717 of the beta-amyloid precursor protein gene, known to be responsible for some cases of familial Alzheimer disease, were not found. Furthermore, coincidental Down syndrome was ruled out by chromosome analysis. The results suggest a possible correlation between this mitochondrial DNA abnormality and Alzheimer-type pathology.
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PMID:Alzheimer-type pathology in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). 887 Aug 35

Alzheimer's disease (AD) is characterized by neuronal cell death and two kinds of deposits, neurofibrillary tangles (NFT) and senile plaques. The main component of NFT is paired helical filaments (PHF), which mainly consist of hyperphosphorylated tau protein. Tau protein kinases I and II were found as candidate enzymes responsible for hyperphosphorylation of tau to induce the formation of PHF. Since prior phosphorylation of tau by TPKII strongly enhanced the action of TPKI, it was thought that TPKII was involved in the formation of PHF-tau in concert with TPKI. After cloning, TPKI was found to be identical with glycogen synthase kinase 3 beta (GSK3 beta), while TPKII consists of a novel 23 kDa protein activator and a catalytic subunit that is identical with cyclin-dependent kinase 5 (CDK5). The phosphorylation sites on tau by TPKI and TPKII could account for the most, but not all, of the major phosphorylation sites of fetal tau and PHF-tau. An antibody for a site specifically phosphorylated by TPKI (Ser413) could identify all three neurofibrillary lesions in the AD brain, and double staining for either TPKI or TPKII and NFT in the brain of Down's syndrome patients clearly demonstrated that TPKI and TPKII are both associated with NFT in vivo, suggesting that the level of TPKI or TPKII is elevated in AD brain by some mechanism. On the other hand, the levels of both TPKs change developmentally, being high in the neonatal period when the phosphorylation of fetal tau proceeds actively, suggesting that the TPKI/TPKII cooperative system has an important physiological role in the formation of neural networks. In AD brain, aberrant accumulation of amyloid-beta protein (A beta) occurs ahead of the accumulation of PHF in NFT. When a primary culture of embryonic rat hippocampus was treated with 20 microM A beta, induction of TPKI, extensive phosphorylation of tau and then programmed cell death were observed, indicating that TPKI induced by A beta phosphorylates tau, followed by disruption of axonal transportation and finally cell death. By using a yeast two hybrid system, TPKI was found to interact with pyruvate dehydrogenase (PDH), which is a key enzyme in the glycolytic pathway. PDH was phosphorylated in vitro by TPKI to reduce the activity converting pyruvate into acetyl-CoA, which is required for acetylcholine synthesis. In a primary culture of rat hippocampal cells treated with A beta, PDH was inactivated in inverse relation to the activation of TPKI, resulting in accumulation of pyruvate or lactate, energy failure induced by the disturbance of glucose metabolism, and a shortage of acetylcholine owing to deficiency of acetyl-CoA, all of which are characteristic of AD brain. In cholinergic neurons such as those of the septum, non-aggregated A beta, specifically A beta (1-42), not A beta (1-40), caused a shortage of acetylcholine by activation of TPKI and inactivation of PDH without cell death.
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PMID:Physiology and pathology of tau protein kinases in relation to Alzheimer's disease. 908 87

Neuropathological findings of Alzheimer's disease (AD) are intracellular (neurofibrillary tangles) and extracellular (senile plaques) filamentous protein aggregates. Non-enzymatic glycation has been proposed as a primary factor in this pathogenesis, leading to increased insolubility of tau protein and beta-amyloid. The aim of our study was to test the hypothesis that increased glycoxidation, i.e. increased levels of oxidized products from non-enzymatic glycation could be found in brains of patients with AD and of aged Down syndrome (DS) subjects with abundant AD-like neuropathological lesions. Frontal cortex specimens were assayed for pentosidine (Pent) and N-epsilon-carboxymethyl-lysine (CML) by reversed phase high performance liquid chromatographical methods. Pent and CML levels in AD (n = 10; Pent, 35.5 +/- 4.84 mumol/g wet-weight tissue; CML, 135.2 +/- 5.0 mumol/g wet-weight tissue) were comparable to DS (n = 9; Pent, 36.4 +/- 3.21; CML, 133.5 +/- 4.7) and controls (n = 10; Pent, 35.2 +/- 3.55; CML, 136.9 +/- 3.3). We conclude that the results are not compatible with the concept of increased glycoxidation in AD compared to normal aging.
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PMID:Evidence against increased glycoxidation in patients with Alzheimer's disease. 929 89

We quantified microtubule-associated protein tau in CSF (CSF tau) using ELISA assay in 168 subjects: 81 patients with clinically diagnosed early Alzheimer's disease (AD), 43 patients with other dementia, 11 Down's syndrome patients, and 33 nondemented neurologic control subjects. Multivariate ANOVA showed an effect of diagnostic group (p < 0.01) and apolipoprotein E (apoE) allele (p < 0.005) on CSF tau. Comparison between diagnostic groups showed higher CSF tau levels in AD than in the control group (p < 0.001). However, CSF tau values in the non-AD dementia group did not differ significantly from those of AD patients or neurologic control subjects. Tau levels were increased (p < 0.005) in AD patients with apolipoprotein E epsilon4 allele, a well-characterized risk factor of AD, compared with AD patients without epsilon4 allele, and the highest values were found in AD patients with two epsilon4 alleles. These increased levels of CSF tau may indicate pronounced neuronal degeneration and neurofibrillar pathology at the early stage of AD in patients carrying the epsilon4 allele. This study shows that the current ELISA test for CSF tau is not sensitive and specific enough to distinguish early AD from other dementias and indicates that in the interpretation of CSF tau analysis as a diagnostic tool, the apoE genotype should also be taken into account.
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PMID:CSF tau is related to apolipoprotein E genotype in early Alzheimer's disease. 944 75


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