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

Abundant neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute one of the defining neuropathological features of Alzheimer's disease. However, tau containing filamentous inclusions in neurones and/or glial cells also define a number of other neurodegenerative disorders clinically characterized by dementia and/or motor syndromes. All these disorders, therefore, are grouped under the generic term of tauopathies. In the first part of this review we outline the morphological and biochemical features of some major tauopathies, e. g. Alzheimer's disease, argyrophilic grain disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. The impact of the recent finding of tau gene mutations in familial frontotemporal dementia and parkinsonism linked to chromosome 17 on other tauopathies is discussed in the second part. The review closes with a look towards a new understanding of neurodegenerative disorders characterized by filamentous nerve cell inclusions. The recent identification of the major protein component of their respective inclusions led to a surprising convergence of seemingly unrelated disorders. The new findings now allow us to classify neurodegenerative disorders with filamentous nerve cell inclusions into four main categories: (i) the tauopathies; (ii) the alpha-synucleinopathies; (iii) the polyglutamine disorders; and (iv) the iquitin disorders'. Within the proposed classification scheme, tauopathies constitute the most frequent type of disorder.
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PMID:REVIEW: tau protein pathology in Alzheimer's disease and related disorders. 1041 59

Alzheimer's disease and Parkinson's disease are the most common neurodegenerative diseases. They are characterized by the degeneration of selected populations of nerve cells that develop filamentous inclusions before degeneration. The neuronal inclusions of Alzheimer's disease are made of the microtubule-associated protein tau, in a hyperphosphorylated state. Recent work has shown that the filamentous inclusions of Parkinson's disease are made of the protein alpha-synuclein and that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene. Besides Parkinson's disease, the filamentous inclusions of two additional neurodegenerative diseases, namely dementia with Lewy bodies and multiple system atrophy, have also been found to be made of alpha-synuclein. Abundant filamentous tau inclusions are not limited to Alzheimer's disease. They are the defining neuropathological characteristic of frontotemporal dementias such as Pick's disease, and of progressive supranuclear palsy and corticobasal degeneration. The recent discovery of mutations in the tau gene in familial forms of frontotemporal dementia has provided a direct link between tau dysfunction and dementing disease. The new work has established that tauopathies and alpha-synucleinopathies account for most late-onset neurodegenerative diseases in man. The formation of intracellular filamentous inclusions might be the gain of toxic function that leads to the demise of affected brain cells.
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PMID:Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies. 1043 13

Neurofibrillary degeneration (NFD) is a degenerating process characterized by the intraneuronal aggregation of abnormal tau proteins. These proteins have a biochemical signature which is disease-specific. They also have a neocortical distribution which is typical of the disease. Pathological tau proteins have been analyzed qualitatively and quantitatively in all diseases that may present the clinical symptoms of frontotemporal dementias. In Alzheimer's disease, a disease with sometimes a frontal predominance, paired helical filaments (PHF) of neurofibrillary tangles are made of hyperphosphorylated tau, named PHF-tau. Their electrophoretic profile consists of four main bands (tau 55, 64, 69, 74 kD), resulting from the presence of the six tau isoforms. In Pick's disease the phosphorylated tau from Pick bodies are made of two major components (tau 55, 64 kD) and a minor 69 kD resulting from the lack of tau isoforms with the translated exon 10 (E10-). Corticobasal degeneration (CBD) also has a different pattern of tau variants, with tau 64, 69 components and a minor tau 74. Pathological tau proteins that aggregate in CBD (and progressive supranuclear palsy) are exclusively made of E10+ tau isoforms. In frontotemporal dementias non-Alzheimer, non-Pick (Lund and Manchester criteria), we did not observe the presence of pathological tau proteins in 2 cases, but a third one presented a particular pattern of tau, with soluble pathological tau in frontotemporal areas. These data show that this group could be heterogeneous. In conclusion, the biochemical signature of tau distinguishes four classes of frontotemporal dementia. The characteristic tau phenotypes observed are linked to the specific neuronal networks that are affected in each disease.
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PMID:Biochemical and molecular characterization of neurofibrillary degeneration in frontotemporal dementias. 1043 46

Perturbations in the microtubule-associated protein tau occur in several human neurodegenerative diseases. In Alzheimer's disease and progressive supranuclear palsy (PSP), tau proteins assemble into straight and paired helical filaments that form intraneuronal deposits of neurofibrillary tangles (NFTs). The mechanisms underlying the aberrant assembly of tau into NFTs is unknown. To determine whether alterations in the expression of the carboxyl-terminal variants of tau contribute to NFT formation, we analyzed tau mRNA isoform expression in select regions of control, Alzheimer's disease, and PSP brains. In Alzheimer's disease, there were no alterations in tau mRNA isoform expression. However, in PSP, the levels of tau mRNA isoforms containing four microtubule binding domains were increased in the brainstem but not the frontal cortex or cerebellum. The brainstem in PSP has extensive NFT pathology, whereas the frontal cortex and cerebellum are relatively spared, suggesting that alterations in tau mRNA isoform expression occur in NFT-vulnerable regions in this disease. An increase in the four-repeat tau mRNA may lead to an increase in four-repeat tau protein isoforms and may contribute to the formation of NFTs in PSP. A similar increase in four-repeat tau mRNA has been reported for mutations associated with frontotemporal dementia and parkinsonism linked to chromosome 17.
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PMID:Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease. 1048 63

Argyrophilic grain disease (AgD), a frequent type of late onset dementia, is characterized by the occurrence of Gallyas-stained neuropil grains in the hippocampus, entorhinal cortex, amygdala and hypothalamus. High numbers of neurons containing hyperphosphorylated tau protein, but devoid of tangles, are encountered in areas rich in argyrophilic grains (ArGs). A third type of change consists of slender argyrophilic and tau-immunoreactive cytoplasmic inclusions in white matter oligodendrocytes, the coiled bodies. We now extend earlier studies on glial pathology in AgD (20 cases) and compare the results with glial changes in old age (10 cases) and Alzheimer's disease (AD; 7 cases). Numerous non-argyrophilic, non-neuronal tau-positive stellate cells in the amygdala and anterior entorhinal cortex were consistently found in all of the 20 AgD cases but not in AD cases. Double-labelling experiments performed on paraffin sections with phosphorylation-dependent anti-tau antibody AT8, anti-glial fibrillary acidic protein and anti-CD44, revealed coexpression of these markers in stellate cells. The high expression of CD44 indicate that they probably correspond to reactive astrocytes. Unlike astrocytic plaques in corticobasal degeneration (CBD), where AT8 reactivity is accumulating in distal astrocytic processes, tau reactivity in AgD was found in all astrocytic cell compartments. The absence of glial fibrillary tangles further distinguished tau-labelled astrocytes in AgD from astrocytic plaques in CBD and tufted astrocytes in progressive supranuclear palsy (PSP). In contrast to AD and aged non-demented control cases tau-positive non-argyrophilic astrocytes represent a consistent finding in anterior limbic structures in AgD. Our findings point to a more widespread pathology of the glial cell population in AgD than previously supposed, and will be of further help in differentiating AgD from other neurodegenerative disorders, including AD, PSP, CBD and Pick's disease.
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PMID:Astrocytes expressing hyperphosphorylated tau protein without glial fibrillary tangles in argyrophilic grain disease. 1048 82

A number of related conditions, including progressive supranuclear palsy (PSP), corticobasal degeneration, Pick's disease, and the parkinsonism dementia complex of Guam, are characterized by the deposition of tau neurofibrillary tangles in the absence of amyloid pathology. These diseases share some overlap in their topography and clinical features but can be subdivided into three main groups according to the isoforms of the alternatively spliced tau gene that are deposited. The recent description of mutation in tau in frontotemporal dementia, and a common variant of tau that predisposes to PSP, and the relationship of these changes to the tau protein subgroups offers new insights into the pathogenesis of these disorders.
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PMID:Neurofibrillary tangle parkinsonian disorders--tau pathology and tau genetics. 1049 33

The cerebellar cortex of progressive supranuclear palsy (PSP) cases exhibited a characteristic pathology which occurred neither in healthy aged individuals nor in cases of fully developed Alzheimer's disease. All of the 11 PSP cases studied reveal altered mossy fiber excrescences containing abnormal and hyperphosphorylated tau protein. Moreover, this abnormal material also appeared in cerebellar oligodendrocytes. Accordingly, there is not only the destruction of the cerebellar output system, which is already known, but also the involvement of the cerebellar input system.
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PMID:Mossy fiber involvement in progressive supranuclear palsy. 1050 37

Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R-tau isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R-tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto-temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.
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PMID:Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. 1051 7

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are usually sporadic multi-system degenerations associated with filamentous tau inclusions in neurons and glia. As such they can be considered sporadic tauopathies in contrast to familial tauopathies linked to mutations in the tau gene. Mutations have not been found in the tau gene in either PSP or CBD. The clinical syndromes and neuroimaging of typical cases of PSP and CBD are distinct; however, atypical cases are described that have overlapping clinical and pathologic features. Both PSP and CBD have similar biochemical alterations in the tau protein, with the abnormal tau protein containing predominantly four-repeat tau. While there is overlap in the pathology in PSP and CBD, there are sufficient differences to continue the present day trend to consider these separate disorders. Several important pathologic features differentiate PSP from CBD. Ballooned neurons are frequent and nearly a sine qua non for CBD, but they are found in PSP at a frequency similar to that of other neurodegenerative diseases, such as Alzheimer's disease. Astrocytic lesions are different, with tufted astrocytes found in motor cortex and striatum in PSP and astrocytic plaques in focal atrophic cortices in CBD. The most characteristic neuronal tau pathology in CBD is wispy, fine filamentous inclusions within neuronal cell bodies, while affected neurons in PSP have compact, dense filamentous aggregates characteristic of globose neurofibrillary tangles. Thread-like processes in gray and white matter are much more numerous and widespread in CBD than in PSP. The brunt of the pathology in CBD is in the cerebrum, while the basal ganglia, diencephalon and brainstem are the targets of PSP. Further clinicopathologic studies will refine our understanding of these disorders and open the possibility that common etiologic factors may be identified for these unusual sporadic tauopathies.
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PMID:Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. 1052 97

Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.
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PMID:The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases. 1053 May 20


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