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)

The two pathological lesions found in the brains of Alzheimer's disease patients, neurofibrillary tangles and neuritic plaques, are likely to be formed through a common pathway. Neurofibrillary tangles are intracellular aggregates of paired helical filaments, the main component of which is hyperphosphorylated forms of the microtubule-associated protein tau. Extracellular neuritic plaques and diffuse and vascular amyloid deposits are aggregates of beta-amyloid protein, a 4-kDa protein derived from the amyloid precursor protein (APP). Using conditions in vitro under which two proline-directed protein kinases, glycogen synthase kinase-3beta (GSK-3beta) and mitogen-activated protein kinase (MAPK), were able to hyperphosphorylate tau, GSK-3beta but not MAPK phosphorylated recombinant APPcyt. The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). This site was confirmed by endoproteinase Glu-C digestion of APPcyt and peptide sequencing. The ability of GSK-3beta to phosphorylate APPcyt and tau provides a putative link between the two lesions and indicates a critical role of GSK-3beta in the pathogenesis of Alzheimer's disease.
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PMID:In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta. 876 98

Alzheimer's disease (AD) is characterized pathologically by two distinguishable deposits in the brain, namely senile plaques and neurofibrillary tangles (NFT). Senile plaques are composed of fragments of the amyloid precursor protein, whereas NFT are composed primarily of paired-helical filaments (PHF). The latter are in turn composed principally of the microtubule-associated protein, tau. Tau in PHF is highly and unusually phosphorylated but the mechanisms leading to this unusual phosphorylation are not known. Using a combination of immunoblotting and kinase assays, we demonstrate that a discreet set of kinases copurify with PHF. One of these kinases was found by immunoblotting to be alpha-calcium-calmodulin-dependent kinase II (alpha-CaM kinase). Immunogold labeling revealed that alpha-CaM kinase was localized to a novel globular membranelike structure found at the ends of PHF. Since previous studies have shown alpha-CaM kinase to be involved in memory, its association with PHF may have important implications in understanding memory loss in AD. We also discuss the possibility that the association of alpha-CaM kinase with PHF may indicate sites where tau protein is converted into PHF.
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PMID:alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer's disease. 880 91

Information on the molecular biology of Alzheimer's disease (AD) pointing to new methods of diagnosis and drug therapies is explored. AD is the most common cause of dementia in the elderly and is characterized by senile plaques and neurofibrillary tangles in the brain and loss of cholinergic neurons in the basal forebrain. The disease has a strong genetic component. A definitive diagnosis can be made only by neuropathologic examination at autopsy or biopsy; however, the accuracy of diagnosis based on standard neuropsychological testing and inclusion criteria has improved considerably. Senile plaques consist of a central core of amyloid fibrils surrounded by dystrophic axons. The main component of senile plaque amyloid is a 39-to 42-amino-acid segment referred to as beta-amyloid, which is derived from amyloid precursor protein (APP). APP exists as multiple isoforms encoded by a single gene on chromosome 21. Factors that may influence APP metabolism include activation of phospholipase C, phosphorylation, and the cholinergic system. The microtubule-associated protein tau may contribute to the neurofibrillary tangles of AD. In AD all six adult isoforms of tau can become maximally phosphorylated and can, rather than binding to microtubules, bind to each other, destabilizing the neuronal cytoskeleton. One of the most important discoveries in AD research was the linking of apolipoprotein E phenotype to familial late-onset AD. Acetylcholinesterase inhibitors appear to improve cognitive function but may be limited in utility by adverse effects. Nicotinic agonists are also being investigated as symptomatic therapies. Other possible strategies include nerve growth factor, agents that potentiate the action of endogenous glutamate, antioxidants, nonsteroidal anti-inflammatory drugs, and estrogens. Research into the molecular biology of Alzheimer's disease has begun to point to possible causes of and treatments for this condition.
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PMID:Molecular basis of Alzheimer's disease. 880 75

Alzheimer's disease, the most frequent cause of dementia, is characterized by the formation in the brain of neurofibrillary tangles and senile plaques. Neurofibrillary tangles are composed of bundles of paired helical filaments containing the microtubule-associated protein tau. In autopsy-derived brain samples from patients with Alzheimer's disease, tau is hyperphosphorylated and constitutes a promising disease marker. Senile plaques contain a small amyloid peptide derived from the amyloid precursor protein. Mutations of the amyloid precursor protein gene have been identified in rare cases of familial Alzheimer's disease, suggesting a causal role for amyloid peptide deposition in the disease. However, Alzheimer's disease has been demonstrated to be characterized by an important genetic heterogeneity. The identification of pathogenic DNA mutations, different from those of the amyloid precursor protein gene, will reveal whether the corresponding genes are involved in either an increased production of the amyloid peptide or a decrease of its removal, or in the fibrillogenic properties of the peptide, which seem to be related to its toxicity. Several mammalian cells are able to produce the amyloid peptide from its precursor. Understanding the cellular mechanisms that determine how cleavages occur in cells could help to identify new strategies for modulating amyloid peptide production. In attempts to produce animal models of Alzheimer's disease, investigators have used transgenic strategies. To date, these efforts have not been very successful. However, the expression in transgenic mice of both mutated amyloid peptide precursor and amyloid associated proteins should prove useful for examining the importance of putative etiological factors, and for testing novel therapies including anti-amyloidogenic strategies.
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PMID:The amyloid peptide and its precursor in Alzheimer's disease. 884 71

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

Paired helical filament (PHF)/tau immunoreactive dystrophic neurites are a common pathological feature in the brain of patients with Alzheimer's disease. Recent studies suggest that swollen neurofilament-immunoreactive neurites are also present in senile plaques. In the present study, we investigated whether PHF/tau-positive dystrophic neurites are located in all subtypes of plaques and whether swollen neurofilament-immunoreactive neurites are hyper-phosphorylated, using a battery of antibodies to PHF/tau, neurofilament, and beta-amyloid protein. PHF/tau-positive dystrophic neurites were present in and around nearly all subtypes of plaques, including small amyloid deposits, diffuse plaques, and perivascular plaques in the hippocampal formation of Alzheimer brain. The earlier changes were detectable with AT8 antibody and later changes with PHF-1 antibody. Plaque-associated PHF/tau-positive dystrophic neurites were rare or absent in the hippocampal formation of normal aged brain. Swollen neurofilament-positive neurites appeared to be hyper-phosphorylated in Alzheimer's disease and to a lesser degree in aged control brains. Neurites that contained hyper-phosphorylated tau as well as neurofilament were strongly argentophilic because both populations of dystrophic neurites stained with silver stains. Swollen neurofilament-positive plaque-associated neurites were often present in the absence of PHF/tau-positive plaque-associated dystrophic neurites. These data suggest that PHF/tau-positive dystrophic neurites are a common component of all subtypes of plaques in Alzheimer brain and neurofilament protein in swollen neurites, like tau protein, is hyper-phosphorylated. Hyper-phosphorylated neurofilaments in plaque-associated neurites may represent one of the earliest cytoskeletal changes in vulnerable neurons in Alzheimer's disease and aged control brains.
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PMID:Plaque biogenesis in brain aging and Alzheimer's disease. I. Progressive changes in phosphorylation states of paired helical filaments and neurofilaments. 895 27

A fusion protein between beta-galactosidase and the amino-terminal domain of amyloid precursor protein (APP) was used as an immunogen for the production of monoclonal antibodies. One of these antibodies, the 5D12 monoclonal antibody, labeled the neurofibrillary tangles (NFT) by immunohistochemistry, as well as isolated paired helical filaments (PHF) in electron microscopy. In immunoassay, the ascitic fluid produced by the 5D12 clone was demonstrated to contain a high titer of antibodies to heat-stable microtubule associated proteins (MAPs). By immunoblotting, the proteins recognized in heat-stable MAPs were found to correspond to tau proteins. The 5D12 antibody recognized normal tau isolated from rat and human brain homogenates, and PHF-tau isolated from the brain of patients with Alzheimer's disease (AD). By immunoblotting, the 5D12 antibody also recognized the full-length recombinant tau protein but not the fusion protein used as an immunogen. The immunoreactivity of the 5D12 antibody with tau was completely abolished when the half-carboxy domain of tau, containing the tubulin-binding repeats, was removed. This study demonstrates that the use of the amino-terminal domain of APP as an immunogen led to the generation of a monoclonal antibody to the half-carboxy domain of tau.
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PMID:Generation of a monoclonal antibody to the carboxy-terminal domain of tau by immunization with the amino-terminal domain of the amyloid precursor protein. 897 5

Cognitive and other behavioural characteristics of 3-month-old heterozygous male transgenic mice expressing the 751-amino acid isoform of human amyloid precursor protein (hAPP751) under the control of a neurone-specific enolase promoter, were compared with those of age-matched non-transgenic control males. No difference was found between hAPP751 transgenics and non-transgenic controls in passive avoidance learning, or in motor coordination. Significantly decreased measures were found in the open field test and in cage activity indicative of general hypoactivity in hAPP751 transgenics. In water maze training, hAPP751 males required significantly longer to locate the hidden platform. This was not due to decreased swimming velocity in hAPP751 mice, but rather to increased path lengths. This suggests a purely spatial learning deficit in hAPP751 males even though their performance during a final spatial test, the probe trail that followed water maze training, was indistinguishable from that of controls. Decreased activity and impaired spatial learning were also reported in an independent study of hAPP751-expressing transgenics showing beta-amyloid immunoreactive deposits and altered tau protein. Since such histopathological alterations were not found in the transgenic model analysed in this study, our results indicate that beta-amyloid deposition is not required for the development of behavioural and/or cognitive deficits in hAPP751 transgenic mice.
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PMID:Spatial learning deficit in mice expressing human 751-amino acid beta-amyloid precursor protein. 898 72

Neurofibrillary tangle (NFT) formation is a feature of postencephalitic Parkinsonism (PEP) and Alzheimer's disease (AD). Tangle formation has been compared immunohistochemically in these 2 conditions. Staining patterns for tau protein, ubiquitin and beta/A4 amyloid protein were studied in frontal lobe, hippocampus, and midbrain in 2 classical cases of PEP, 2 cases of AD and 2 controls matched for age and sex. NFTs were present in all cases, but with varying frequency: all tangles were tau-positive and many were ubiquitinated. In the frontal cortex and hippocampus, irrespective of the case category, tangle formation was associated with beta/A4 amyloid deposition. A similar association was present in the 2 AD cases in the midbrain. However, in PEP tangle formation in the midbrain was not associated with adjacent beta/A4 amyloid deposition. This finding raises the possibility that the pathogenetic mechanism of tangle formation in PEP is different from that of AD, although the final cellular morphological expression of abnormality in both conditions is similar.
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PMID:An immunohistochemical study of neurofibrillary tangle formation in post-encephalitic Parkinsonism. 899 52

A variety of measures of neuropathology in Alzheimer's disease (AD) correlate with dementia severity. However, the role of beta-amyloid protein and abnormally phosphorylated tau protein in the decline of specific cognitive abilities is unknown. "Constructional praxis' (e.g., copying, constructing) is believed to require integrity of the parietal-occipital lobes. Unlike most other cognitive tasks, some AD patients are able to perform some constructional tasks even late in the disease course. Thus, it may be an ideal task to evaluate the relationship between various measures of AD neuropathology and cognitive performance. Fixed brain tissue was obtained from 16 AD patients who were cognitively assessed shortly before death. Parietal, frontal, entorhinal, and occipital cortices were examined by immunocytochemistry for beta-amyloid protein and abnormally phosphorylated tau protein at both early and later stages of neuropil thread and tangle formation. Constructional praxis in AD was strongly related to early-stage tau hyperphosphorylation in occipital cortex. Praxis ability was specific in that it was not significantly related to pathology in other areas and non-constructive tasks were not associated with occipital cortex pathology. In contrast, global dementia severity was related to beta-amyloid deposition in entorhinal, parietal, and frontal regions. These findings suggest that occipital cortex is critical for some constructional praxis tasks and that some regionally localizable tasks may be good indices of underlying pathology in corresponding brain regions.
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PMID:Constructional apraxia in Alzheimer's disease correlates with neuritic neuropathology in occipital cortex. 900 34


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