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)

Pick's disease chiefly is characterized by progressive degeneration of specific telencephalic cortical areas and associated subcortical nuclei. Components of the cerebellum also are affected. Immunoreactions for abnormally hyperphosphorylated tau protein, indicating the development of cytoskeletal anomalies in a few susceptible neuroectodermal cell types, permit visualization and identification of the pathology. Initially, accumulations of nonargyrophilic material appear in the perikarya and cellular processes of susceptible nerve cells. In some neuronal types, the abnormal deposits are transformed into more condensed inclusions, so-called Pick bodies in perikarya and Pick neurites in cellular processes, some of which become argyrophilic in the course of the disease. This study employs silver techniques and immunoreactions to draw attention to Pick's disease-associated lesions in the cerebellar cortex and cerebellar nuclei. Immunoreactive rosettes, which correspond to the terminal synaptic boutons of mossy fibers, frequently are encountered in the cerebellar granule cell layer. Some cases of Pick's disease also exhibit afflicted monodendritic brush cells in this layer. Single immunopositive Purkinje cells occasionally are seen as well. The brunt of the alterations is borne by cerebellar subdivisions receiving dense input from the telencephalic cortex through the pontocerebellar pathway (neocerebellum). The dentate nucleus shows immunoreactive axons with numerous varicose thickenings which remain confined to the reaches of this band-like nuclear gray and probably represent collaterals of altered mossy fibers. A large number of the dentate projection cells also contain the abnormal material in the perikarya, as well as in all of the neuronal processes. Many of these cells develop spherical nonargyrophilic condensations of this material. Output of the neocerebellum is conveyed to extended territories of the telencephalic cortex via the dentate nucleus and thalamus. Therefore, all of the cerebellar territories which receive major input from and generate output chiefly to the telencephalic cortex (pontocerebellum or neocerebellum) are notably afflicted in Pick's disease. Other subdivisions with preponderant input from the spinal cord and/or other noncortical sources remain intact or else are only minimally involved. It is concluded that the pattern of cerebellar involvement reflects Pick's disease-associated neocortical destruction.
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PMID:Cerebellar involvement in Pick's disease: affliction of mossy fibers, monodendritic brush cells, and dentate projection neurons. 1048 84

This study examines a sex-dependent variant of neurofibrillary pathology recently identified in the hypothalamus of elderly human males. Here we focus upon the relationship between the sex-dependent hypothalamic changes and Alzheimer's disease (AD)-related neurofibrillary pathology. To this end, autopsy brains of 31 males (mean age 84.1 years) and 26 age-matched females (mean age 86.7 years) were examined. Both the male and the female subjects exhibited either particularly mild (stage I) or fully developed (stage V) AD-related neurofibrillary brain pathology. Serial 100-micron hypothalamic sections were cut in the frontal plane and stained for hyperphosphorylated tau protein using the monoclonal antibody AT8. Argyrophilic neurofibrillary pathology was demonstrated using a modified Gallyas silver-iodide technique. A conspicuous pathology, characterized by neurofibrillary tangles, a network of dystrophic neurites, and terminal-like vessel-associated processes, was identified in the infundibular nucleus which is located in the mediobasal tuber cinereum. This pathology was noted in 20 males (64.5%), but did not occur in the female group. No statistically significant correlation was noted between the degree of sex-dependent pathology and the presence of AD-related cortical pathology. In particular, the expression of the sex-dependent changes did not differ between males with AD stage I and males with AD stage V. In summary, the existence of a sex-dependent variant of neurofibrillary pathology was confirmed. In addition, our findings strongly suggest that the sex-dependent changes develop independently of the neurofibrillary changes associated with senile dementia of the Alzheimer type. Instead, the sex-dependent hypothalamic pathology probably corresponds to a distinct neurodegenerative entity preferentially affecting elderly males.
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PMID:Sex-dependent cytoskeletal changes of the human hypothalamus develop independently of Alzheimer's disease. 1063 Feb 3

Intracellular filamentous inclusions containing abnormally phosphorylated tau protein are hallmarks of several human neurodegenerative disorders. This study reveals tau-positive cytoskeletal abnormalities in neurons and glial cells of aged baboons. The brains of four baboons (Papio hamadryas, 20-30 yr of age) were examined using the Gallyas silver technique for neurofibrillary changes and phosphorylation-dependent anti-tau antibodies (AT8, AT100, AT270, PHF-1, TG-3). Conspicuous changes were noted in two animals, 26 and 30 yr of age. In both animals, a combination of neuronal and glial cytoskeletal pathology was seen preferentially affecting limbic brain areas, including the hippocampal formation. In the 30-yr-old animal, numerous tau-positive inclusions were seen in the granule cells of the fascia dentata. These cells even exhibited an accumulation of argyrophilic neurofibrillary tangles. The glial changes affected both astrocytes and oligodendrocytes. Tau-positive astrocytes were seen in perivascular, subpial, and subependymal locations. Tau-positive oligodendrocytes preferentially occurred in limbic fiber tracts including the entorhinal perforant path. Ultrastructurally, tau-positive straight filaments (10-14 nm) in both neurons and glial cells were revealed by anti-tau immunoelectron microscopy. This study thus indicates the potential usefulness of aged baboons for experimental investigation of neuronal and glial filamentous tau pathology. This nonhuman primate species may provide valuable information pertinent to the broad spectrum of human tauopathies.
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PMID:Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons. 1074 34

This study examines the evolution of Alzheimer's disease (AD)-related pathology in a subcortical predilection site, the basal nucleus of Meynert (bnM), which is a major source of cortical cholinergic innervation. Brains of 51 autopsy cases were studied using silver techniques and immunostaining for tau-associated neurofibrillary pathology and for amyloid beta protein (Abeta) deposits. All cases are classified according to a procedure permitting differentiation of six stages of AD-related neurofibrillary changes in the cerebral cortex. Initial cytoskeletal abnormalities in the bnM are already noted in stage I of cortical neurofibrillary changes. The gradual development of the neurofibrillary pathology in the bnM parallels the progression of the AD-related stages in the cerebral cortex. A variety of morphologically distinguishable cytoskeletal alterations are observed in large nerve cells which predominate in the bnM. Based on these cellular alterations, a sequence of cytoskeletal deterioration is proposed. Initially, the abnormal tau protein is distributed diffusely throughout the cell body and the neuronal processes. Subsequently, it aggregates to form a neurofibrillary tangle, which appears as a spherical somatic inclusion. The cell processes gradually become fragmented. Finally the parent cell dies, leaving behind an extraneuronal "ghost tangle". With regard to the cortical stages of AD-related neurofibrillary changes, the initial forms of cytoskeletal changes in the bnM predominate in the transentorhinal AD stages (I and II), while "ghost tangles" preferentially occur in the neocortical stages (V and VI). The considerable morphological diversity of cytoskeletal alterations is typical of stages III and IV. These results indicate that individual neurons of the bnM enter the sequence of cytoskeletal deterioration at different times.
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PMID:Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert. 1096 95

Thiazin red (TR), a fluorochrome that has an affinity to fibrillary structures such as neurofibrillary tangles (NFTs) or senile plaques, was utilized to investigate assembly of tau protein into fibrils in tau-immunopositive neocortical neurons of corticobasal degeneration (CBD) and of Alzheimer's disease (AD). Double fluorescence with anti-paired helical filament monoclonal antibody (AT8) and TR was followed by either the Gallyas or Bodian silver impregnation method, which enabled a comparison of the staining features by three different methods on the same neuron. NFTs of AD were uniformly stained by TR and Gallyas method. Most of tau-immunopositive neurons of CBD were similarly stained by Gallyas method but barely or only weakly by TR or Bodian method, suggesting that tau in neocortical neurons of CBD is less liable to form fibrillary structures than in those of AD, easily distinguishable by TR staining. Clarifying the process of tau assembly using this fluorochrome will give a clue to understanding mechanisms of tau deposition, which may be different in various neurological disorders.
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PMID:Tau-positive neurons in corticobasal degeneration and Alzheimer's disease--distinction by thiazin red and silver impregnations. 1098 96

Mutations in the microtubule-associated protein tau, including P301L, are genetically coupled to hereditary frontotemporal dementia with parkinsonism linked to chromosome 17. To determine whether P301L is associated with fibril formation in mice, we expressed the longest human tau isoform, human tau40, with this mutation in transgenic mice by using the neuron-specific mouse Thy1.2 promoter. We obtained mice with high expression of human P301L tau in cortical and hippocampal neurons. Accumulated tau was hyperphosphorylated and translocated from axonal to somatodendritic compartments and was accompanied by astrocytosis and neuronal apoptosis indicated by terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end-labeling staining. Moreover, P301L tau formed abnormal filaments. Electron microscopy of sarcosyl-insoluble protein extracts established that the filaments had a straight or twisted structure of variable length and were approximately 15 nm wide. Immunoelcecton microscopy showed that the tau filaments were phosphorylated at the TG3, AT100, AT8, and AD199 epitopes in vivo. In cortex, brain stem, and spinal cord, neurofibrillary tangles were also identified by thioflavin-S fluorescent microscopy and Gallyas silver stains. Together, our results show that expression of the P301L mutation in mice causes neuronal lesions that are similar to those seen in human tauopathies.
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PMID:Tau filament formation in transgenic mice expressing P301L tau. 1101 46

Pick's and Alzheimer's diseases are distinct neurodegenerative disorders both characterized in part by the presence of intracellular filamentous tau protein inclusions. The tight bundles of paired helical filaments (PHFs) of tau protein found in Alzheimer's disease (AD) differ from the tau filaments of Pick's disease in their morphology, distribution, and pathological structure as identified by silver impregnation. The filaments of Pick's disease are loosely arranged in pathognomonic spherical inclusions found in ballooned neurons, whereas the tau pathology of AD is classically described as a triad of neuropil threads, neurofibrillary tangles, and dystrophic neurites surrounding and invading plaques. In this study we used the high-resolution technique of scanning transmission electron microscopy to characterize and compare the filaments found in Pick's disease with those found in AD. In addition, we determined the mass/nm length and density of arachidonic acid-induced in vitro-assembled filaments. Three morphologically distinct populations of Pick's filaments were identified but each was indistinguishable from AD-PHFs in mass/nm length and density. Filaments assembled in vitro from single isoforms were similar in mass/nm length, but less dense than AD-PHFs and Pick's disease filaments. Finally, we provide clear structural evidence that a PHF, whether found in disease or assembled in vitro, is composed of two distinct intertwined filaments.
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PMID:Structural analysis of Pick's disease-derived and in vitro-assembled tau filaments. 1129 May 66

Frontal dementia is a clinical entity of cognitive impairment, characterized mostly by progressive loss of fluency in speech, eventually resulting in aphasia or anomia, associated frequently with early loss of insight and many forms of inappropriate behavior. Hyperphosphorylation of the isoforms of tau protein, a microtubule-associated protein, which plays an important role in the pathogenetic mechanisms of Alzheimer's disease, is mainly involved in the pathogenesis of frontal dementia. In the present study, the morphological alterations of the acoustic cortex are described in three cases of dementia who fulfilled all the clinical and neuropathological criteria of frontal dementia. Specimens from the acoustic area of the temporal cortex were processed with Golgi silver impregnation techniques, Cajal and Rio Hortega stainings and electron microscopy. A tremendous loss of Cajal-Retzius neurons in layer I of the acoustic cortex was noticed in Golgi staining, associated with dense reactive astrocytosis, visualized clearly in Cajal gold impregnation technique. Loss of dendritic spines was extensively seen in layers III, V, and VI in correlation with normal controls. The electron microscopy revealed numerous Pick bodies, whose tau protein was the main protein constituent. Paired helical filaments were seen in the perikaryon and the axons of the neurons of layers IV, V, and VI. Synaptic alterations were extensively seen in the acoustic cortex consisting mainly of degeneration of the postsynaptic components. The authors think that the impressive morphological alterations of the acoustic cortex in frontal dementia might explain the early onset of deficiency of communication that most of the patients demonstrate in the initial stage of the disease.
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PMID:The acoustic cortex in frontal dementia. 1134 98

We studied the brain of a patient with pallidonigroluysian atrophy (PNLA) in whom argyrophilic and abnormally phosphorylated tau positive neurons and glia were identified in the brain on Gallyas-Braak silver staining and immunohistochemical analysis although neurofibrillary tangles were not seen by Bodian silver stain. Immunohistochemical studies using six anti-tau antibodies that recognize the different phosphorylated epitopes of tau protein revealed that these epitopes in neurons and glial cells share common characteristics with neurofibrillary tangles in Alzheimer's disease. Immunoblot analysis of phosphorylated tau protein showed major bands of 64 and 68 kDa and after dephosphorylation, tau consisted mainly of 4 repeat tau. No mutations were detected in the coding exons and their flanking intronic regions of the tau gene. This study suggests that PNLA is one of tauopathy and the biochemical characteristics of phosphorylated tau are similar to those found in progressive supranuclear palsy and corticobasal degeneration.
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PMID:Tau accumulation in a patient with pallidonigroluysian atrophy. 1150 52

Niemann-Pick type C (NPC) disease is a fatal hereditary neurovisceral disorder with diagnostically relevant intracellular accumulation of cholesterol in non-brain tissue, for example the spleen and fibroblasts. In the brain, many ballooned neurons are seen. Using filipin microfluorodensitometry, significant accumulations of free cholesterol in specified neurons have been described in NPC patients. The present study demonstrates spatial and temporal accumulation of free cholesterol in the brains of homozygous NPC (-(npc)/-(npc)) mice, a widely acknowledged mouse model, and in primarily cultured neurons therefrom. Intraneuronal storage of free cholesterol was already prominent at a pre-clinical stage in various grey matter areas of the murine cerebral cortex. Hippocampal areas showed differential development of the pathological distribution of free cholesterol. The pyramidal cells in the CA3 sector of Ammon's horn were affected much earlier than in CA1. Some of the deeper cerebral nuclei were affected only slightly, even at the final stage. Neurons (E15-E17) cultured in a cholesterol-free medium also showed massive accumulation of intracellular free cholesterol. In addition, brains from the murine NPC model for Alzheimer's disease (AD)-like changes in the microtubule-associated protein tau were tested using the Gallyas silver technique and AT8-immunolabelling, since both human diseases are accompanied by intraneuronal tangles made up of tau protein aggregations. Although the analysis failed to show classical silver-stainable tangles of the AD type in the NPC mice, tau protein phosphorylated at epitopes considered to represent early stages of AD was found. This further strengthens the concept that an alteration in cholesterol metabolism may play an important role in AD. The NPC mouse model may thus serve as a tool to analyse the role of cholesterol in initial changes of tau that eventually lead to the formation of tangles in both NPC and AD.
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PMID:Spatial and temporal distribution of intracellular free cholesterol in brains of a Niemann-Pick type C mouse model showing hyperphosphorylated tau protein. Implications for Alzheimer's disease. 1269 47


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