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 Chamorro population of the island of Guam is highly susceptible to a disease called lytico-bodig (LB), which clinically resembles a mixture of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer disease (AD). The disease is characterized by the widespread development of neurofibrillary tangles in the central nervous system. These tangles have an immunohistochemical profile indistinguishable from that seen in AD. We studied by immunohistochemistry the occurrence of intracellular and extracellular neurofibrillary tangles in LB in the entorhinal cortex, hippocampus and substantia nigra using antibodies to tau protein and ubiquitin. We also studied the relationship of these tangles to amyloid precursor protein (APP) and its beta-amyloid fragment (BAP), using multiple antibodies to BAP and other APP sequences. In advanced cases of LB, the development of neurofibrillary tangles was far more severe than in advanced cases of AD. Virtually all neurons of CA-1 and the subiculum were lost and only ghost tangles remained. In areas dominated by such extracellular tangles, BAP deposits were frequently observed developing around the fibers of ghost tangles. In some cases, the deposits covered only a few of the fibers, but in others, they seemed to envelope the complete tangle. The deposits were thioflavin S and Congo red positive, indicating that the BAP was in a consolidated form. We describe these entities as "tangle-associated amyloid deposits". Such BAP deposits have previously been described in some cases of AD, dementia pugilistica and LB. However, we found them in all cases of LB with dementia in the hippocampal-entorhinal areas and in most cases in the substantia nigra. They do not evolve from diffuse BAP deposits since they are remote from them, and they do not trap dystrophic neurites. The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further consideration needs to be given to the ways in which extracellular BAP deposits are formed.
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PMID:Relationship of amyloid beta/A4 protein to the neurofibrillary tangles in Guamanian parkinsonism-dementia. 852 3

Deposition of PrP amyloid in cerebral vessels in conjunction with neurofibrillary lesions is the neuropathologic hallmark of the dementia associated with a stop mutation at codon 145 of PRNP, the gene encoding the prion protein (PrP). In this disorder, the vascular amyloid in tissue sections and the approximately 7.5-kDa fragment extracted from amyloid are labeled by antibodies to epitopes located in the PrP sequence including amino acids 90-147. Amyloid-laden vessels are also labeled by antibodies against the C terminus, suggesting that PrP from the normal allele is involved in the pathologic process. Abundant neurofibrillary lesions are present in the cerebral gray matter. They are composed of paired helical filaments, are labeled with antibodies that recognize multiple phosphorylation sites in tau protein, and are similar to those observed in Alzheimer disease. A PrP cerebral amyloid angiopathy has not been reported in diseases caused by PRNP mutations or in human transmissible spongiform encephalopathies; we propose to name this phenotype PrP cerebral amyloid angiopathy (PrP-CAA).
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PMID:Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. 857 Jun 27

Abundant neurofibrillary tangles, neuropil threads and senile plaque neurites constitute the neurofibrillary pathology of Alzheimer's disease. They form in the nerve cells that undergo degeneration in the disease, in which their regional distribution correlates with the degree of dementia. Each lesion contains the paired helical filament (PHF) as its major component. PHFs are composed of the microtubule-associated protein tau in a hyperphosphorylated state. PHF-tau is hyperphosphorylated on all six adult brain isoforms. As a consequence, tau is unable to bind to microtubules and is believed to self-assemble into the PHF. Several candidate protein kinases and protein phosphatases have been identified through in vitro experiments.
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PMID:Tau protein and the neurofibrillary pathology of Alzheimer's disease. 862 74

Significant developments in our understanding of the pathophysiology of Alzheimer's disease have been obtained in the recent years. Diagnostic criteria, based on clinical data, have been proposed and have been validated by clinico-pathological correlations. Some neuroimaging techniques and laboratory tests (e.g. dosage in the cerebrospinal fluid) are promising diagnostic avenues. Genetic mutations associated with familial cases of the disease have been identified and the involved genes localized on chromosome 1, 14 or 21. The apolipoprotein E genotype has been discovered to affect the risk of developing the disease, i.e. homozygotes for the apolipoprotein E4 allele are much more prone to develop Alzheimer's disease The definitive diagnosis of the disease still relies on the demonstration of characteristic neuropathological lesions, i.e. neurofibrillary tangles and senile plaques, whose numbers are correlated with the severity of the dementia. Other lesions include neuronal and synaptic loss, amyloid angiopathy, and severe decrease in the level of cortical acetylcholine. Neurofibrillary tangles have been found to be composed of the microtubule-associated protein tau, in highly phosphorylated state. The accumulation of these phosphorylated tau proteins is thought to be associated to disturbances of intracellular transport of molecules and organelles in affected neurones, leading to cell dysfunction and death. An inbalance in the activities of selected protein kinases and phosphatases is also thought to generate these highly phosphorylated tau species. The major component of senile plaques is the A4/beta amyloid peptide, generated by proteolysis of the amyloid peptide precursor, a transmembrane protein. When aggregated into amyloid fibrils, the A4/beta amyloid peptide is thought to be neurotoxic. An abnormal metabolism of the amyloid peptide precursor is often considered as a central physiopathological mechanism of the disease. Although many pharmacological treatments of the disease have been investigated, they have not yet led to sustained and major clinical improvements.
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PMID:The neurobiology of Alzheimer's disease. 869 72

Cerebrospinal fluid (CSF) biochemical markers for Alzheimer disease (AD) would be of great value to improve the clinical diagnostic accuracy of the disorder. As abnormally phosphorylated forms of the microtubule-associated protein tau have been consistently found in the brains of AD patients, and since tau can be detected in CSF, two assays based on several well-defined monoclonal tau antibodies were used to study these proteins in CSF. One assay detects most normal and abnormal forms of tau (CSF-tau), while the other is highly specific for phosphorylated tau (CSF-PHFtau). A marked increase in CSF-PHFtau was found in AD (2230 +/- 930 pg/mL), as compared with controls (640 +/- 230 pg/mL; p < 0.0001), vascular dementia, VAD (1610 +/- 840 pg/mL; p < 0.05), frontal lobe dementia, FLD (1530 +/- 1000 pg/mL; p < 0.05), Parkinson disease, PD (720 +/- 590 pg/mL; p < 0.0001), and patients with major depression (230 +/- 130 pg/mL; p < 0.0001). Parallel results were obtained for CSF-tau. No less than 35/40 (88%) of AD patients had a CSF-PHFtau value higher than the cutoff level of 1140 pg/mL in controls. The present study demonstrates that elevated tau/PHFtau levels are consistently found in CSF of AD patients. However, a considerable overlap is still present with other forms of dementia, both VAD and FLD. CSF-tau and CSF-PHFtau may therefore be useful as a positive biochemical marker, to discriminate AD from normal aging, PD, and depressive pseudodementia. Further studies are needed to clarify the sensitivity and specificity of these assays, including follow-up studies with neuropathological examinations.
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PMID:Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? 874 26

A 57-year-old man had exhibited cortical sensory disturbance, rigidity, spasticity, dementia, alien hand, grasp reflex, supranuclear ophthalmoplegia, pseudobulbar palsy, and neck dystonia for 4 years. Histological examination of autopsied specimens revealed neuronal loss in the cerebral cortex, with ballooned neurons, subthalamic nucleus, substantia nigra, basal ganglia, midbrain tegmentum, and the thalamus. There were neurofibrillary tangles in the subthalamic nucleus and the substantia nigra. Gallyas-Braak silver impregnation demonstrated numerous argentophilic tangles, threads, and a few argentophilic glia in the cerebral cortex, subcortical white matter, particularly in the precentral gyrus, subcortical nuclei, and the brainstem. These argentophilic structures were largely positive for tau, and negative for ubiquitin, paired helical filaments, and phosphorylated neurofilament. Ultrastructurally, 15-nm-wide straight tubules were observed in the neurons of the substantia nigra, globus pallidus, and the precentral cortex, coexisting with a few twisted tubules periodically constricted at 160- to 230-nm intervals. It was conclusively shown that Gallyas- and tau-positive cytoskeletal abnormalities occurred widely in brain of corticobasal degeneration. Both distribution and morphology of abnormal phosphorylated tau protein in corticobasal degeneration appear to resemble these features in progressive supranuclear palsy. These findings suggest a common cytoskeletal etiopathological significance in corticobasal degeneration and progressive supranuclear palsy.
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PMID:Corticobasal degeneration: widespread argentophilic threads and glia in addition to neurofibrillary tangles. Similarities of cytoskeletal abnormalities in corticobasal degeneration and progressive supranuclear palsy. 879 Dec 41

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 (AD) is characterised neuropathologically by the presence of abundant extracellular beta-amyloid deposits and intracellular neurofibrillary lesions consisting of neurofibrillary tangles, neuropil threads and senile plaque neurites which contain paired helical filaments (PHFs) made of hyperphosphorylated microtubule-associated protein tau. A new familial form of presenile dementia with neurofibrillary pathology and no beta-amyloid deposits has been described recently [Sumi et al. (1992) Neurology 42: 120-127]. We have compared the tau pathology in this familial form of presenile dementia with that of AD. To this end we have used electron microscopy, immunoblotting and immunohistochemistry with phosphorylation-dependent (PHF1, AT8, AT100, AT180, AT270, 12E8) and phosphorylation-independent (BR133, BR134) anti-tau antibodies. We show that in the two diseases dispersed PHFs are structurally, biochemically and immunologically identical; they are stained by all anti-tau antibodies used and on immunoblots PHF-tau appears as three major bands of 60, 64 and 68 kDa. However, while the anti-tau antibodies stain neurofibrillary tangles, neuropil threads and neuritic plaques in AD brain, no neuritic plaques are found in familial presenile dementia. These results indicate that in the two diseases tau undergoes the same modifications; they confirm that neurofibrillary tangles and neuropil threads like those in AD can exist independently of beta-amyloid deposits and that their presence is associated with dementia.
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PMID:Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles. 881 Nov 24

Apolipoprotein E (Apo E) has been recently identified within amyloid deposits and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. A strong association of the Apo E epsilon 4 allele with higher risk of developing AD has also been reported. In the present study, the distribution of Apo E and the possible relationship between Apo E alleles and neuropathological alterations were analyzed in a series of Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) cases, a neurodegenerative condition characterized neuropathologically by widespread, severe neurofibrillary tangle formation but rare amyloid deposits. ApoE immunoreactivity was consistently observed in both type of lesions in these cases. Compared to tau protein immunoreactivity, there were generally fewer Apo E-immunoreactive neurofibrillary tangles, particularly in the deep layers of the neocortex and in the hippocampus. Genotype analysis revealed that the epsilon 4 allele frequency was 5.9%, the epsilon 3 allele frequency 88.2%, and the epsilon 2 allele frequency 5.9% in this series. Recent data suggest that the Apo E4 variant may induce amyloidogenesis, while E2 could have a neuroprotective role. However, the rare Guamanian patients with amyloid deposits in cortical areas were not related to the epsilon 4 allele, since all cases with senile plaques were epsilon 3/epsilon 3. In addition, compared to unaffected Guamanian cases and other Asian-Pacific populations previously reported, the observed low frequency of the epsilon 2 allele in the present cases, which may be consistent with the notion that this allele, may represent a neuroprotective factor in several neurodegenerative disorders. The present data indicate that there is a strong interaction between Apo E deposition and neurofibrillary changes in Guamanian ALS-PDC.
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PMID:Apolipoprotein E in Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex: genotype analysis and relationships to neuropathological changes. 883 36

Increasing use of immunocytochemistry for evaluation of dementia disorders has revealed histopathological alterations that were previously unknown, even with sensitive silver techniques. Disorders [Pick's disease (PD), diffuse Lewy body disease (DLBD) and corticobasal degeneration (CBD)] in which immunocytochemistry has revealed occult pathology are discussed. All three disorders have neurofilament (NF) immunoreactive neuronal alterations in the neocortex. In DLBD round, eosinophilic cytoplasmic inclusions referred to as cortical Lewy bodies are neurofilament-positive, while in both PD and CBD neurofilament epitopes are expressed in irregularly swollen neurons and their proximal cell processes, which are referred to as ballooned neurons. Interestingly, the cortical neuronal population that is vulnerable to Lewy bodies is similar to that which is vulnerable to ballooned neurons. Furthermore, Lewy bodies can occasionally be detected within the cytoplasm of ballooned neurons. Besides neurofilament-immunoreactivity, Lewy bodies are immunoreactive for ubiquitin, while ballooned neurons are inconsistently stained with antibodies to ubiquitin. Both Lewy bodies and ballooned neurons can be appreciated with routine histology, but they are much easier to detect with immunocytochemistry. In contrast, a new type of neuritic alteration in the hippocampal CA2/3 region has been recognized in DLBD. These dystrophic neurites cannot be appreciated with routine histology and are only optimally seen with immunocytochemistry for ubiquitin. Their presence is a certain indication of the presence of cortical Lewy bodies. The microtuble associated protein tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD). Biochemical studies have shown that Pick bodies, argyrophilic neuronal inclusions that are highly characteristic of, if not pathognomonic for PD are also composed of abnormal tau protein. Along with Pick bodies, tau has recently been detected in glial cells in PD. Similar so-called "gliofibrillary tangles" are increasingly recognized in progressive supranuclear palsy. Previously, CBD was considered to be free of such lesions, but recent studies have revealed widespread tau-positive neuronal and glial cytoskeletal lesions in CBD. A distinctive type of tau-positive glial lesion in CBD is characterized by annular clusters of grain-like tau immunoreactivity reminiscent of a neuritic plaque in AD, except that the clusters are devoid of amyloid. The tau-positive profiles are consistently located around a central astrocyte cell body. Double labeling studies with glial fibrillary acidic protein, vimentin and CD44, which are markers for reactive astrocytes, demonstrates tau immunoreactivity within astrocytic processes; these "astrocytic plaques" appear to be specific for CBD. Although NF, ubiquitin and tau proteins are present in diverse neuronal and glial inclusions in these disorders, the morphology and distribution of these lesions differentiate non-AD dementias.
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PMID:Cytoskeletal pathology in non-Alzheimer degenerative dementia: new lesions in diffuse Lewy body disease, Pick's disease, and corticobasal degeneration. 884 55


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