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)

An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty-eight affected individuals were identified with an age of onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD score of 2.87. Affected individuals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced. This analysis included the microtubule-associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.
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PMID:Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22. 939 79

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

We examined a 65-year-old patient with clinicopathological features that met the criteria of frontotemporal dementia (FTD), particularly frontal lobe degeneration (FLD). He came from a family with concentrated occurrence of dementia symptoms in the presenium. Neuropathological examination disclosed brain atrophy locally pronounced on the frontotemporal lobes with characteristic neuronal loss, microvacuolation and astrocytic gliosis. There were no pathological hallmarks such as senile plaques, Pick bodies (PBs), achromatic cells and neurofibrillary tangles. Precise separation of FTD from Pick disease (PD) and motor neuron disease with dementia (MNDD) has not yet been established, and they are included in one spectrum. Antibodies against paired helical filament tau protein demonstrated immunopositive cytoskeletal structures within the neurons as well as the glial cells in the brain of the present case. They were selectively stained with tau 199/202 but not tau 396, which were provided newly to recognize phosphorylation at Ser 199/202 or Ser 396 in tau, respectively. We investigated tau pathology in the present case in comparison to 8 cases with PD that were clinicopathologically confirmed. Neither tau 199/202 nor tau 396 stained the CNS structures in PD cases with few PBs, while both stained evidently those as well as PBs in PD cases associated with many PBs; so that the present case could be distinguished from PD on the basis of the immunoreactivity to site-specific phosphorylated tau. Our result suggests that FTD, especially familial FLD type might involve unique tau pathology, no matter whether FLD is a distinct entity from PD, or a variant form in the wide FTD spectrum including PD and MNDD and other related disorders.
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PMID:Selective expression of Ser 199/202 phosphorylated tau in a case of frontotemporal dementia. 952 99

Frontotemporal dementia is a neurological disorder characterised by personality changes, deterioration of memory and executive functions as well as stereotypical behaviour. Sometimes a Parkinsonian syndrome is prominent. Several cases of frontotemporal dementia are hereditary and recently families have been identified where the disease is linked to chromosome 17q21-22. Although, there is clinical and neuropathological variability among and within families, they all consistently present a symptomathology that has led investigators to name the disease "Frontotemporal Dementia and Parkinsonism linked to chromosome 17." Neuropathologically, these patients present with atrophy of frontal and temporal cortex as well as of basal ganglia and substantia nigra. In the majority of cases these features are accompanied by neuronal loss, gliosis and microtubule-associated protein tau deposits which can be present in both neurones and glial cells. The distribution, structural and biochemical characteristics of the tau deposits differentiate them from those present in Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy and Pick's disease. No beta-amyloid deposits are present. The clinical and neuropathological features of the disease in these families suggest that Frontotemporal Dementia and Parkinsonism linked to chromosome 17 is a distinct disorder. The presence of abundant tau deposits in the majority of these families define this disorder as a new tauopathy.
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PMID:Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. 954 95

While clinicopathological studies have confirmed that Alzheimer's disease (AD) is the most common neurodegenerative cause of dementia, these same studies have also revealed that other degenerative pathologies account for a significant proportion of patients with cognitive decline. Because pathological assessment of non-Alzheimer neurodegenerative diseases now demands routine use of a costly panel of immunohistochemical techniques a scheme for staged examination of brain tissue has been developed. This scheme is weighted to initially screen out cases of Alzheimer's disease, dementia with Lewy bodies and vascular dementia using conventional staining methods and established diagnostic protocols, bringing in immunochemical techniques to discriminate between non-Alzheimer degenerative dementias. Diagnosis of pathologies causing the clinical syndrome of frontotemporal dementia can be ascertained using conventional staining supplemented by immunochemical detection of ubiquitin, tau protein and alpha beta crystallin. The diagnosis of prion disease is reliably confirmed by immunohistochemical detection of prion protein. This morphological assessment complements emerging genetic insights into many of these neurodegenerative diseases.
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PMID:Establishing a pathological diagnosis in degenerative dementias. 954 96

Braak's argyrophilic grains (ArGs) are spindle-shaped neuropil structures originally found in patients afflicted with adult onset dementia. We recently observed that tau protein is hyperphosphorylated in most nerve cells in areas rich in ArGs, suggesting that these grains may be a morphological expression of tau protein pathology in local neurons. The aim of this study was therefore to determine in three cases with ArGs whether grains are associated with individual neurons containing hyperphosphorylated tau. A combination of Gallyas silver staining and AT8 immunocytochemistry was used. AT8 is a monoclonal antibody that recognizes tau in a phosphorylation-dependent manner. Up to 80% of pyramidal cells of sector CA1 showed diffuse AT8 staining of their cell bodies and dendrites. Most grains were freely scattered throughout the neuropil. However, some were clearly located in side-branches of apical dendrites of AT8 immunoreactive pyramidal neurons. Dendritic branches often formed bush-like ramifications containing clusters of ArGs. Other dendrites consisted of a single stump containing one or two large grains at their tips. Spheroidal enlargements of dendritic branches, with a size corresponding to ArGs, were also found in Golgi Cox preparations of cases with ArGs but not in Alzheimer's disease cases or in controls. Our results show that some ArGs are formed within dendrites of neurons whose most obvious pathology is a diffuse hyperphosphorylation of the tau protein. Furthermore, morphology of dendrites containing grains suggests that a process of progressive shrinkage of dendrites is taking place in neurons bearing ArGs.
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PMID:Argyrophilic grains of Braak: occurrence in dendrites of neurons containing hyperphosphorylated tau protein. 954 29

The neuropathological diagnosis of Alzheimer disease relies on the presence of both neurofibrillary tangles and senile plaques. The number of neurofibrillary tangles is tightly linked to the degree of dementia, suggesting that the formation of neurofibrillary tangles more directly correlates with neuronal dysfunction. The regional pattern of areas affected by neurofibrillary tangle formation during the course of the disease is relatively stereotyped. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated protein tau. Phosphorylated tau proteins accumulate early in neurones, even before formation of neurofibrillary tangles, suggesting that an imbalance between the activities of protein kinases and phosphatases acting on tau is an early phenomenom. The latter might be related to changes in signalling through transduction cascades, since many of the protein kinases generating phosphorylated tau species participate in signalling pathways. The accumulation of neurofibrillary tangles and phosphorylated tau species is associated with disturbances of the microtubule network, and, as a consequence of the latter, of axoplasmic flows. The mechanistic relationship between the formation of neurofibrillary tangles and senile plaques is still poorly understood and in vivo formation of neurofibrillary tangles in experimental models has not yet been achieved. Future animal models, e.g. transgenic animals expressing combined key human proteins, will hopefully faithfully reproduce all the major cellular lesions of the disease.
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PMID:The role of neurofibrillary tangles in Alzheimer disease. 968 75

In view of existing drugs (acetylcholine esterase inhibitors) and emerging therapeutic compounds (e.g. neuroprotective and anti-inflammatory compounds), CSF markers would be of great use to improve the clinical diagnostic accuracy of Alzheimer's disease (AD). Correct identification of AD would be especially important early in the course of the disease, when the clinical diagnosis is difficult, and drugs have the greatest potential of being effective. Biochemical markers for AD include ApoE genotyping, where the ApoE epsilon 4 allele has proven to have a high predictive value for AD. Biochemical markers for AD also include several potential cerebrospinal fluid (CSF) markers: beta-amyloid(1-42), possibly reflecting amyloid deposition and formation of senile plaques; PHFtau protein a marker for the phosphorylation state of tau, and formation of neurofibrillary tangles; (total)tau protein, a normal axonal protein, as a marker for ongoing neuronal and axonal degeneration; synaptic vesicle proteins, e.g. synaptotagmin, a synaptic vesicle protein which is found in the CSF, as markers for synaptic activity or degeneration; neuromodulin or growth-associated protein GAP-43, as a marker for synaptic degeneration, and the CSF/serum albumin ratio, as a marker for blood-brain barrier damage, used to exclude patients with concomitant cerebrovascular pathology. However, although CSF markers may identify different pathogenic processes in AD, there is no such process that is specific for AD, and thus little hope of ever finding a single CSF biochemical marker that gives an absolute discrimination between AD and other dementia disorders. Instead, combination of several CSF biochemical markers, each reflecting a pathogenic process, may increase both the sensitivity and specificity. Further, the accuracy of the clinical diagnosis of AD may increase if the diagnosis is based on the summarised information gained from the clinical examination, brain-imaging techniques (SPECT, CT/MRT scans), and biochemical markers. Using this approach, CSF markers have a large potential to help to differentiate AD from the most problematic differential diagnoses, especially age-associated memory impairment, depressive pseudo-dementia, Parkinson's disease, and frontal lobe dementia.
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PMID:Combination of the different biological markers for increasing specificity of in vivo Alzheimer's testing. 970 Jun 60

Frontotemporal dementia and parkinsonism (FTDP) is the second most common cause of neurodegenerative dementia after Alzheimer's disease. Recently, several kindreds with an autosomal dominant form of FTDP have been reported and in some families the pathological locus was mapped to a 2 cM interval on 17q21-22. The MAPT gene, located on 17q21 and coding for the human microtubule-associated protein tau, is a strong candidate gene, since tau-positive neuronal inclusions have been observed in brains from some FTDP patients. Direct sequencing of the MAPT exonic sequences in 21 French FTDP families revealed in six index cases the same missense mutation in exon 10 resulting in a Pro-->Leu change at amino acid 301. Co-segregation of this mutation with the disease was demonstrated by restriction fragment analysis in two families for which several affected relatives were available. The Pro301Leu mutation was not observed in either 50 unrelated French controls or in 11 patients with sporadic frontotemporal dementia. This mutation, which occurs in the second microtubule-binding domain of the MAPT protein, is likely to have a drastic functional consequence. The observation of this mutation in several FTDP families might suggest that disruption of binding of MAPT protein to the microtubule is a key event in the pathogenesis of FTDP.
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PMID:Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. 973 86

The neuropathological diagnosis of Alzheimer's disease relies on the presence of both neurofibrillary tangles and senile plaques. The number of neurofibrillary tangles is tightly linked to the degree of dementia, suggesting that the formation of neurofibrillary tangles more directly correlates with neuronal dysfunction. The regional pattern of areas affected by neurofibrillary tangles formation during the course of the disease is relatively stereotyped. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated protein tau. Phosphorylated tau proteins accumulate early in neurons, even before formation of neurofibrillary tangles, suggesting that an imbalance between the activities of protein kinases and phosphatases acting on tau is an early phenomenon. The latter might be related to changes in signalling through transduction cascades, since many of the protein kinases generating phosphorylated tau species participate in signalling pathways. The accumulation of neurofibrillary tangles and phosphorylated tau species is associated with disturbances of the microtubule network and, as a consequence of the latter, of axoplasmic flows. The mechanistic relationship between the formation of neurofibrillary tangles and senile plaques is still little understood and in vivo formation of neurofibrillary tangles in experimental models has not yet been achieved. Future animal models, e.g. transgenic animals expressing combined key human proteins, will hopefully reproduce faithfully all the major cellular lesions of the disease.
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PMID:Neurofibrillary tangles and Alzheimer's disease. 974 70


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