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)

Population studies have established that one of the common isoforms of apolipoprotein E, the apoE4, is associated with higher incidence and earlier age of onset of late onset familial Alzheimer's disease (AD), whereas apoE2 may have the opposite effect. The apoE3 and apoE4 isoforms were shown to display different binding reactivities with amyloid beta peptide (Abeta) and tau protein in vitro. On the basis of these findings, it has been proposed that the apoE isoforms may modulate positively or negatively the formation of either the neurofibrillary tangles or the amyloid deposits in the brain of patients with AD. To study the interaction of Abeta with nascent apoE isoforms we have expressed their cDNAs in baby hamster kidney (BHK-21) cells using the Semliki Forest Virus expression system. Analysis of the secreted apoE by one- and two-dimensional gel electrophoresis and immunoblotting showed that the nascent apoE is heavily modified with carbohydrate chains containing sialic acid. A dimeric form of apoE is formed with apoE2 and apoE3 but not with apoE4 isoforms. Analysis of the interaction of nascent apoE2, apoE3, and apoE4 produced by BHK-21 cells with Abeta (1-40) under physiological conditions (pH 7.4, 37 degrees C) showed that the efficiency of the apoE monomer-Abeta complex formation follows the order apoE2 > apoE3 >> apoE4. In addition, the apoE2 dimer formed a complex with Abeta more efficiently than the apoE3 dimer. The isoform-specific differences in binding were temperature-dependent and are attenuated upon decrease of the temperature. The binding behavior of the monomeric apoE is different from that reported for plasma apoE3 and apoE4 or commercially available apoE3 and apoE4 preparations and similar to that described for apoE3 and apoE4 produced by human embryonic kidney (HEK-293) cells. It appears that the efficiency of binding between each of three main apoE isoforms and Abeta correlates inversely with the risk of developing late-onset familial AD and may indicate possible involvement of apoE in the binding and clearance of Abeta in vivo.
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PMID:Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer's disease. 926 39

Alzheimer's disease (AD) represents a heterogeneous disorder, and several factors have been associated with its development. The presence of the apolipoprotein E type (APOE) epsilon 4 allele has been proposed as a risk factor for AD, but how it influences the development of the characteristic hallmarks of the disease remains unknown. In the present study, the neuropathological changes and levels of both core PHF-tau and normal tau protein in 4 neocortical areas, cerebellum and medial temporal cortex were determined in 18 AD cases. The extent of these changes was compared between 10 cases possessing an epsilon 4 allele and 8 cases without. These two groups were indistinguishable in terms of neurofibrillary pathology, whereas cases with an epsilon 4 allele had more diffuse plaques, particularly in the temporal neocortex. Biochemically, there was no difference in the levels of PHF-tau protein between the two groups. These data indicate that APOE epsilon 4 allele may influence deposition of diffuse amyloid, but altered tau protein processing, which underlies the development of the neurofibrillary pathology in AD, is not influenced by this allele.
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PMID:Presence of the apolipoprotein E type epsilon 4 allele is not associated with neurofibrillary pathology or biochemical changes to tau protein. 929 30

We quantified microtubule-associated protein tau in CSF (CSF tau) using ELISA assay in 168 subjects: 81 patients with clinically diagnosed early Alzheimer's disease (AD), 43 patients with other dementia, 11 Down's syndrome patients, and 33 nondemented neurologic control subjects. Multivariate ANOVA showed an effect of diagnostic group (p < 0.01) and apolipoprotein E (apoE) allele (p < 0.005) on CSF tau. Comparison between diagnostic groups showed higher CSF tau levels in AD than in the control group (p < 0.001). However, CSF tau values in the non-AD dementia group did not differ significantly from those of AD patients or neurologic control subjects. Tau levels were increased (p < 0.005) in AD patients with apolipoprotein E epsilon4 allele, a well-characterized risk factor of AD, compared with AD patients without epsilon4 allele, and the highest values were found in AD patients with two epsilon4 alleles. These increased levels of CSF tau may indicate pronounced neuronal degeneration and neurofibrillar pathology at the early stage of AD in patients carrying the epsilon4 allele. This study shows that the current ELISA test for CSF tau is not sensitive and specific enough to distinguish early AD from other dementias and indicates that in the interpretation of CSF tau analysis as a diagnostic tool, the apoE genotype should also be taken into account.
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PMID:CSF tau is related to apolipoprotein E genotype in early Alzheimer's disease. 944 75

Previous studies have shown that treating rat cortical neurons in primary culture with apolipoprotein E (apoE) peptide increased cytoplasmic Ca2+ by 2 mechanisms: 1) an influx of extracellular Ca2+ resulting from the activation of a cell surface Ca2+ channel; and 2) release of Ca2+ from internal Ca2+ stores via a G-protein-coupled pathway (Wang and Gruenstein, 1997). These studies employed a biologically active apoE synthetic peptide (apoEdp) derived from the receptor binding domain of apoE. In the present study we examined whether activation of these 2 signal transduction pathways affects phosphorylation of microtubule-associated protein tau. The levels of tau phosphorylation at thr231, ser235, and ser396 were quantified by ELISA employing monoclonal antibodies PHF-6, SMI33, and PHF-1. ApoEdp treatment resulted in a concentration- and time-dependent dephosphorylation of tau at all 3 phosphorylation sites. The apoEdp-induced dephosphorylation of tau at thr231, and ser235 was dependent on the influx of extracellular Ca2+, while dephosphorylation at ser396 was mediated by a pertusis toxin-sensitive G-protein pathway. The involvement of protein phosphatases in mediating the apoEdp-induced dephosphorylation of tau was examined. Pretreatment with the protein phosphatase 2B inhibitor cyclosporin A blocked the apoEdp-induced dephosphorylation of tau at thr231 and ser235 but not at ser396. Pretreatment with the protein phosophatase 2A/1 inhibitor okadaic acid blocked the apoEdp-induced dephosphorylation of tau at all 3 sites, while pretreatment with the protein phosphates 1 inhibitor tautomycin was without effect. The present study suggests that apoE may affect several Ca2+-associated signal transduction pathways that increase the activity of protein phosphatases 2A and 2B, which in turn dephosphorylate tau.
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PMID:Apolipoprotein E (ApoE) peptide regulates tau phosphorylation via two different signaling pathways. 951 10

Tau-positive inclusions that occur in glial cells are called glial fibrillary tangles or, more simply, glial tangles. These include tuft-shaped astrocytes, thorn-shaped astrocytes, coiled bodies, and argyrophilic threads. The latter two structures occur in oligodendroglia. The tau protein in glial tangles is hyperphosphorylated and has similar immunohistochemical profiles to that in neurofibrillary tangles (NFTs) except that there are no epitopes derived from alternatively spliced exon 2 and 3. In contrast to NFTs, glial tangles rarely show solid filaments. Such NFT-associated molecules as ubiquitin, apolipoprotein E, alpha1-antichymotrypsin, and heparan sulfate are all absent from glial tangles. These characteristics suggest that glial tangles resemble the pre-tangles that occur in neurons and are thought to represent an early stage of NFTs. Tau pathology in neurodegenerative diseases takes heterogenous forms.
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PMID:Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. 956 75

Argyrophilic grain disease (AGD) is a distinct degenerative disorder of the human brain associated with the formation of abnormally phosphorylated tau protein. AGD-related cytoskeletal changes are known to affect specific subsets of nerve cells and oligodendrocytes. Here we demonstrate a remarkable association between the apolipoprotein E (ApoE) epsilon2 allele and AGD. Individuals afflicted with AGD (n = 48) reveal a significantly higher frequency of the epsilon2 allele compared with controls (n = 43) (22% versus 4%, P < 0.0002). The association between AGD and epsilon2 allele of ApoE suggests that AGD can be distinguished from other neurodegenerative disorders not only neuropathologically, but also genetically.
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PMID:Argyrophilic grain disease is associated with apolipoprotein E epsilon 2 allele. 975 52

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.
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PMID:Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. 977 46

The diagnosis, genetics, risk factors, neuropathology, and pathogenesis of Alzheimer's disease (AD) are discussed. AD is a degenerative brain disorder and is the leading cause of dementia. Clinical manifestations of AD are primarily the progressive loss of memory and language. Other signs and symptoms of the disease include psychiatric and behavioral disturbances and impairments in the performance of activities of daily living (ADL). To diagnose AD, other causes of dementia-- some of which may be reversible--must be ruled out by laboratory testing and neuroimaging. The pathogenic process that causes AD has not been fully delineated; however, it clearly leads to neuropathology characterized by neuritic plaques, neurofibrillary tangles, and loss of cholinergic neurons in the nucleus basalis of Meynert. Genetic factors, including mutations in the amyloid precursor protein and the two presenilin genes, appear important in the development of early-onset familial AD, whereas the apolipoprotein E genotype influences the timing of disease onset after age 65. Genetic factors may promote or accelerate deposition of beta-amyloid protein to form plaques, as well as abnormal phosphorylation of tau protein to form neurofibrillary tangles. Several biochemical factors, such as inflammation, oxidative stress, and hormonal deficiency (estrogen), and other unmodifiable risk factors, notably aging, also play a role in the pathogenic process. The loss of neurons and synaptic connections is selective and causes deficiencies in cholinergic and other neurotransmitter systems, leading to cognitive dysfunction, psychiatric and behavioral disturbances, and eventual loss of ability to perform ADL. The etiology and pathogenesis of AD are highly complex; more effective therapeutic approaches than those currently available will be needed to address these underlying factors more specifically.
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PMID:Etiology and pathogenesis of Alzheimer's disease. 980 5

The main lesions of Alzheimer's disease are: 1. amyloid deposits, labelled by antibodies directed against the A beta peptide (core of the senile plaques, diffuse deposits and amyloid angiopathy), 2. neurofibrillary lesions labelled by anti-tau antibodies (neurofibrillary tangles, neuropil threads, crown of the senile plaques) and 3. loss of neurons and synapses. The distribution of neurofibrillary pathology is hierarchical: they begin in the entorhinal cortex, progress along the anterograde corticocortical pathways toward the multimodal and unimodal associative cortices to reach, in the most severe cases, the primary cortices. Amyloid lesions are more diffuse, rapidly affecting all the cortical areas. The density of neurofibrillary tangles in the cerebral cortex is correlated with the severity of dementia. Neuritic plaques, synaptic and neuronal loss also contribute to the intellectual deterioration. There are various causes of Alzheimer's disease (several mutations, trisomy 21, repeated head trauma as in dementia pugilistica): it should be considered a syndrome. Its pathophysiology is complex and involves several proteins (e.g. amyloid protein precursor, tau protein, presenilins 1 and 2, and apolipoprotein E).
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PMID:[Brain lesions, pathogenic and etiologic hypotheses of Alzheimer's disease]. 985 88

The concentration of tau protein in cerebrospinal fluid (CSF) was determined in 40 patients with clinically diagnosed probable Alzheimer disease (AD) and in 36 cognitively healthy controls. A significant increase of CSF tau was found in the AD patients, even in 19 subjects with very mild dementia as defined by a Mini-Mental State Examination score of 25 and above. Using a cutoff value of 260 pg/mL the sensitivity of elevated tau was 0.89, the specificity was 0.97, and the proportion of correctly allocated cases was 95%. In the AD groups there were no significant associations between CSF tau level and age, age at onset, duration of illness, apolipoprotein E genotype, severity of cognitive impairment, or deficit in regional cerebral blood flow as measured using 99Tm-ethyl cystein dimer single photon emission computed tomography. The findings demonstrate that CSF tau is significantly increased at the earliest clinical stage of AD and shows only minimal overlap with age-matched cognitively healthy controls. This finding suggests that CSF tau could be a biological marker of AD even before dementia has developed.
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PMID:Tau protein in cerebrospinal fluid is significantly increased at the earliest clinical stage of Alzheimer disease. 987 68


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