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's Disease (AD) is a progressive neurodegenerative disorder involving select neurons of the hippocampus, neocortex, and other regions of the brain. Markers of end stage disease include fibrillar lesions, which accumulate hyperphosphorylated tau protein polymerized into filaments, and granulovacuolar lesions, which appear primarily within the hippocampus. The mechanism by which only select populations of neurons develop these lesions as well as the relationship between them is unknown. To address these questions, we have turned to AD tissue to search for enzymes specifically involved in tau hyperphosphorylation. Recently, we showed that the principal phosphotransferases associated with AD brain-derived tau filaments are members of the casein kinase-1 (CK1) family of protein kinases. Here we report the distribution of three CK1 isoforms (Ckialpha, Ckidelta, and Ckiepsilon) in AD and control brains using immunohistochemistry and Western analysis. In addition to colocalizing with elements of the fibrillar pathology, CK1 is found within the matrix of granulovacuolar degeneration bodies. Furthermore, levels of all CK1 isoforms are elevated in the CA1 region of AD hippocampus relative to controls, with one isoform, Ckidelta, being elevated >30-fold. We propose that overexpression of this protein kinase family plays a key role in the hyperphosphorylation of tau and in the formation of AD-related pathology.
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PMID:A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer's disease. 1051 99

Within neurofibrillary tangles and dystrophic neurites of Alzheimer's disease (AD), tau protein is hyperphosphorylated. In the present study, we provide evidence that acute injection of okadaic acid (1 mM, 0.5 microliter) into the dorsal hippocampus induces the formation of paired helical filament (PHF)-1, sternberger monoclonals incorporated (SMI)-31, and amyloid precursor protein (APP) positive dystrophic neurites in the lacunosum-molecular layer of CA1 and molecular layer of dentate gyrus. Okadaic acid evoked a marked loss of microtubule associated protein (MAP)-2 immunoreactivity. PHF-1 immunoreactive terminals were fine, and SMI-31 immunoreactive terminals appeared at granular terminals and at the ring-like or elongated dystrophic neurites. APP positive dystrophic neurites exhibited large bulb-like globular terminals. Interestingly, APP dystrophic neurites were co-localized with SMI-31 immunoreactivity in the core. APP immunoreactivity became stronger over 24 h even in vehicle injected area. These results may provide the morphological evidence for the animal model to study dystrophic neurites formation of AD.
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PMID:The formation of PHF-1 and SMI-31 positive dystrophic neurites in rat hippocampus following acute injection of okadaic acid. 1071 93

A number of pathological changes have been reported in relation to CA1 pyramidal cells in Alzheimer's disease (AD), among them hyperphosphorylation of tau protein followed by the formation of filamentous tau lesions, granulovacuolar degeneration (GVD), Hirano bodies and spindle-shaped dilatations of distal apical dendrites. Juxtacellular clusters of glutamate receptor (GluR)-positive granules around pyramidal cells of the CA1 sector have been recently reported under the term "non-plaque dystrophic dendrites". We independently found that CA1 pyramidal cells in AD patients are regularly surrounded by ubiquitin-positive granules measuring 1-4 microns in diameter, which we have termed perisomatic granules (PSG). Using confocal microscopy, ubiquitin- and GluR-reactive granules were found to largely coincide and to correspond to the same structure. By immunoelectron microscopy PSG were found to consist of GluR1-2-reactive enlarged synaptic boutons containing tubulo-filamentous or floccular material. PSG were found to be consistently associated with pyramidal (principal) cells but not with interneurons of the CA1 sector. Dual-labeling experiments have shown that PSG are preferentially associated with tau-immunoreactive "pretangle" neurons but not with cells containing filamentous tau inclusions or with tau-negative nerve cell bodies. The number of PSG was found to increase with the severity of AD changes with almost no PSG found in Braak stages I and II and few in stage III. Furthermore, PSG were not AD specific, as shown by their presence around CA1 pyramidal cells in Pick's disease. The reasons for GluR reactivity and ubiquitin complex formation in enlarged perisomatic boutons are unclear. Marked changes in GluR subunits have been observed in association with even moderate AD pathology in hippocampal pyramidal cells in AD and our findings suggest a pathogenic link between PSG and early tau pathology in CA1 neurons. PSG might represent residual and abnormally clustered GluR subunits in degenerating perisomatic neurites. Our work confirms and extend previous study on perisomatic "non-plaque dystrophic dendrites" in AD and establish PSG as a pathological entity distinct from GVD. In addition PSG should be acknowledged among main histological changes associated with hippocampal neurons in AD and Pick's disease.
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PMID:Perisomatic granules (non-plaque dystrophic dendrites) of hippocampal CA1 neurons in Alzheimer's disease and Pick's disease: a lesion distinct from granulovacuolar degeneration. 1176 25

Argyrophilic grain disease (AgD) is a late-onset dementia morphologically characterized by abundant neuropil grains (ArGs). ArGs are mainly found in the CA1 subfield of the cornu ammonis, entorhinal and transentorhinal cortices, the amygdala and the hypothalamic lateral tuberal nuclei. We have recently shown that abnormally phosphosphorylated tau protein is the main protein constituent of ArGs and that tau is hyperphosphorylated in up to 80p.100 of nerve cels in areas rich in ArGs. We could demonstrate that at least a subset of grains are formed within dendrites and dendritic side-branches of neurons containing hyperphosphylated tau. Morphology of dendrites containing grains suggests that a process of progressive dendritic shrinkage is taking place in neurons bearing ArGs. Furthermore it became apparent that the presence of ArGs is not necessarily associated with a cognitive decline. Our studies on AgD cases with and without dementia suggest that AgD is a progressive neurodegenerative disorder with early subclinical lesions in anterior part of the hippocampal formation. At later stages involvement of more caudal parts of the hippocampal formation generally results in a cognitive decline. Thus, one possible explanation for the dementia observed in some subjects with AgD is that there is a more widepread loss of postsynaptic structures, including synaptic contacts, throughout the hippocampus-entorhinal/parahippocampal complex and the amygdaloid nuclei. Most of the reported AgD cases are associated with neurofibrillary lesions (e.g. neurofibrillary tangles) which are also typical of Alzheimer's disease (AD). However, neurofibrillary changes do not exceed early (entorhinal and limbic) Braak stages which generally are not associated with a cognitive decline. Additional neuropathological features of AgD include oligodendroglial tau filamentous inclusions ( coiled bodies ), ballooned neurons and astrocytic tau pathology. The clinical features of AgD are poorly understood. However, preliminary data from retrospective studies suggest that in AgD behavioural disturbances will precede memory failure and memory decline. Furthermore, it has been shown that the ApoEe4 allele does not constitute a risk factor for the development of AgD. In conclusion it seems very likely that AgD is a distinct dementing disorder of old age that has to be distinguished from other tauopathies, e.g. AD, by both morphological and genetic criteria.
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PMID:[Argyrophilic grain disease (AgD), a frequent and largely underestimated cause of dementia in old patients]. 1196 71

The cellular distribution of malondialdehyde (MDA) was assessed immunohistochemically in brain specimens from young and normal elderly subjects as well as patients with Alzheimer's disease (AD). MDA was increased in the cytoplasm of neurons and astrocytes in both normal aging and AD, but was rarely detected in normal young subjects. By electron microscopic immunohistochemistry, neuronal MDA formed cap-like linear deposits associated with lipofuscin, while glial MDA deposits surrounded the vacuoles in a linear distribution. In the hippocampus, neuronal and glial MDA deposition was marked in the CA4 region but mild in CA1. By examination of serial sections stained with anti-MDA and antibodies against an advanced glycation end product, N(epsilon)-(carboxymethyl)lysine (CML), neuronal and glial MDA deposition was colocalized with CML in AD, but only neuronal MDA was colocalized with CML in normal aged brains. Glial MDA, although abundant in the aged brain, typically was not colocalized with CML. In AD cases, MDA was colocalized with tau protein in CA2 hippocampal neurons; such colocalization was rare in CA1. MDA also was stained in cores of senile plaques. Thus, while both MDA and CML accumulate under oxidative stress, CML accumulation is largely limited to neurons, in normal aging, while MDA also accumulates in glia. In AD, both MDA and CML are deposited in both astrocytes and neurons.
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PMID:Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease. 1211 53

The clinical and neuropathological features in the P301L tauopathy have been described in several kindreds. In this study, we present findings in two previously unreported patients, evaluated both genetically, neuropathologically, and with multiparametric confocal immunofluorescence. The patients were female, with age 65 and 75 years old, respectively. Both exhibited clinical symptoms of frontotemporal dementia (FTD). Marked atrophy of the frontal and temporal lobes with moderate atrophy of the remaining cerebral and brain stem structures was present. The substantia nigra was pale. The atrophic neocortical regions exhibited neuronal loss, marked gliosis, status spongiosus, and occasional ballooned neurons. By light microscopy, the most striking findings were argyrophilic perinuclear rings, frequently with an attached small inclusion (mini Pick-like body), especially prominent in dentate granule cells, entorhinal and temporal cortices, and to a lesser extent in CA1. These structures were immunopositive for tau protein (Tau-2, AT-8, PHF-1, MC-1). Numerous astrocytic plaques, tuft-shaped astrocytes, coiled bodies, and dystrophic neurites were also present. Confocal immunofluorescence with a P301L-specific antibody directly demonstrated the presence of the mutated protein in the PHF-1 positive aggregates. The mutated tau protein (4-repeat tau) was detected in the mini Pick-like bodies, indicating an important biochemical difference between these inclusions and classical Pick bodies (3-repeat tau). Additionally, since 4-repeat tau protein is not normally present in dentate granule cells, this result also suggests an abnormality in the mRNA splicing mechanisms. The structural features of the involvement of proteolytic systems in this tauopathy were assessed by immunohistochemistry for the active form of calpain II (C-27) and ubiquitin. Colocalization of PHF-1 positive aggregates with C-27 points to the possible involvement of calpain in tau protein hyperphosphorylation. Absence of immunostaining for ubiquitin indicates possible dysfunction of the ubiquitin-proteasome system in this tauopathy.
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PMID:P301L tauopathy: confocal immunofluorescence study of perinuclear aggregation of the mutated protein. 1212 82

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

Neurofibrillary pathology [paired helical filaments (PHFs)] formed by the microtubule-associated protein tau in a hyperphosphorylated form is a major hallmark of Alzheimer's disease and related disorders. The process of tau phosphorylation, thought to be of critical importance for PHF formation, and its potential link to neurodegeneration, however, is not understood very well, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. Here we describe the formation of highly phosphorylated tau, containing a number of PHF-like epitopes in torpor during hibernation. PHF-like phosphorylation of tau was not associated with fibril formation and was fully reversible after arousal. Distribution of PHF-like tau followed a consistent pattern, being most intense in the entorhinal cortex, hippocampus, and isocortical areas. Within the hippocampus, a particularly high labeling was seen in CA3 pyramidal cells. Somewhat lesser reactivity was present in CA1 neurons while dentate gyrus granule cells were not reactive. Formation of PHF-like tau in CA3 neurons was paralleled by the regression of synaptic contacts of the mossy fiber system terminating on CA3 apical dendrites. Mossy fiber afferentation was re-established during arousal, concomitantly with the decrease of PHF-like tau in CA3 neurons. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau. The repeated formation and degradation of PHF-like tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. Hibernation will, therefore, be a valuable model to study the regulation of PHF-like tau-phosphorylation and its cell biological sequelae under physiological in vivo conditions.
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PMID:Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. 1290 58

Oxidative stress has been implicated in the pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM). N epsilon-carboxymethyllysine (CML) is an advanced glycation end product (AGE) recently found to be associated with oxidative stress mechanisms. Using immunocytochemical methods we examined the distribution of CML in brain tissue from AD and DM subjects and aging controls. CML reactivity was present in the cytoplasm of neurons, but there were marked differences in the intensity of expression, number of cells, and topographical distribution. CML expression was higher in hippocampus than in frontal and temporal cortex. In the hippocampus, neuronal and, to an extent, glial expression was more marked in CA3 and CA4 than in CA1 and CA2. In AD, CML was found to be coexpressed with tau protein, showing the similar neurofibrillary tangle shape, as well as in neuritic plaques but not in the core of amyloid plaques. We noted an increasing degree of CML expression such that the highest reactivity was evident in those with both AD and DM, followed by AD, DM, and aging controls. There was an inverse relationship between Braak staging and topography of CML expression. Although DM cases did not show Abeta deposition or neurofibrillary tangles, these findings suggest increased CML expression is not limited to AD. Nonetheless, high CML expression in AD with coexistent DM suggests there are additive effects compared with AD alone. It is plausible that the microangiopathy also associated with DM could worsen AD pathogenesis.
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PMID:N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease. 1511 Mar 89

We performed proteomic analysis of neurofibrillary tangles (NFTs) obtained by laser capture microdissection from pyramidal neurons in hippocampal sector CA1 in patients with Alzheimer disease (AD) using liquid chromatography (LC)-mass spectrometry (MS)/MS. We discovered a total of 155 proteins in laser captured NFT's, 72 of which were identified by multiple unique peptides. Of these 72 proteins, 63 had previously unknown association with NFTs; one of these was glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We validated by immunohistochemistry that GAPDH co-localized with the majority of NFTs as well as plaque-like structures in AD brain and was co-immunoprecipitated by antibodies to abnormal forms of tau in AD, but not tau from AD temporal cortex. Characterization of GAPDH showed that it, along with phosphorylated tau and Abeta peptides, was present in detergent-insoluble fractions from AD temporal cortex but not from age-matched controls. These data are the first proteomic investigation of NFTs. Moreover, our results validate this approach by demonstrating that GAPDH, a glycolytic and microtubule binding protein, not only co-localized to NFTs and immunoprecipitated with PHF-tau, but also is one of the few proteins known to undergo conversion to a detergent-insoluble form in AD.
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PMID:Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament tau binding protein. 1574 84


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