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)

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

This report concerns an investigation on ubiquitin immunoreactivity in the neuronal perikarya of hippocampal granular cells in Guamanian amyotrophic lateral sclerosis (G-ALS) and Guamanian parkinsonism-dementia complex (G-PDC). Specimens from two non-Guamanian cases of ALS with dementia (ALS-D) were included for comparison. Histologically normal hippocampi from five adults served as controls. Antibodies to ubiquitin and tau protein were used throughout. Most Guamanian patients examined had granular cells with perikaryal ubiquitin immunoreactivity in the dentate gyrus, but in comparison to ALS-D, the frequency of ubiquitin-positive neurons was significantly lower. Tau-positive granular cells were detected in most Guamanian patients, but not in ALS-D. There was a relationship between the numbers of ubiquitin-positive and tau-positive neurons in the dentate granular cell layer of G-ALS and G-PDC patients. This was verified on sections double immunostained for tau protein and ubiquitin. The present findings suggest that the ubiquitin-positive materials observed in the perikarya of the dentate granular cells of patients with G-ALS or with G-PDC seem to be Alzheimer's neurofibrillary tangles rather than the typical ubiquitin-positive intracytoplasmic neuronal inclusions, characteristics of ALS-D. Our data would indicate that different mechanisms are involved in the geneses of cortical neuronal degeneration and decline in cognitive function in ALS-D, G-ALS and G-PDC.
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PMID:Comparative study of ubiquitin immunoreactivity of hippocampal granular cells in amyotrophic lateral sclerosis with dementia, Guamanian amyotrophic lateral sclerosis and Guamanian parkinsonism-dementia complex. 908 58

The Hohara village of the Kii peninsula is one of the high incidence ALS foci, and the high incidence was reported to have ended in early 1980s. However, we have found the ALS incidence rate has been still high, more than 100 times of the other areas of Japan. In addition, we have found many cases of parkinsonism-dementia complex (PDC). ALS and PDC often occur simultaneously in a single patient or in a single family. Family history was positive in more than 70% of patients. ALS and PDC showed common neuropathological findings consisting of ALS pathology and many neurofibrillary tangles (NFT) without senile plagues, and isoform pattern of NFT tau protein was similar to that of Alzheimer disease (AD), but different from that of progressive supranuclear palsy (PSP) or Pick's disease (PiD). Kii ALS/PDC may be a novel tauopathy that differ from AD, PSP or PiD.
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PMID:[Amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii Peninsula of Japan]. 1278 69

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula (Kii ALS/PDC) is a neurodegenerative disorder endemic to natives in the southern coast area of the Kii peninsula of Japan. The disorder closely resembles Guamanian ALS/PDC clinically and neuropathologically. The characteristic neuropathological finding is abundant neurofibrillary tangles (NFTs) without amyloid deposition. To elucidate the biochemical properties of hyperphosphorylated tau protein, the major component of the NFTs, we examined Kii ALS/PDC brains by immunoblotting and immunohistochemical analysis using well-characterized anti-tau antibodies specific to phosphorylation-dependent or -independent epitopes. Hyperphosphorylated tau in Kii ALS/PDC had phosphorylated epitopes common to tau of paired helical filaments (PHFs) in Alzheimer disease (AD): immunoblot showed triplet bands composed of 6 tau isoforms. Ultrastructurally, NFTs revealed a twisted filamentous shape similar to PHF of AD. The biochemical properties of its phosphorylated tau protein and the ultrastructural characteristics of the NFTs of Kii ALS/PDC are very similar, if not identical, to PHF tau in AD, although they are different taupopathies.
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PMID:Biochemical and ultrastructural study of neurofibrillary tangles in amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula of Japan. 1290 4

The authors have characterized frontal cortical tau protein in cognitively intact (4) and cognitively impaired (ALSci, 4) ALS patients and compared it with control (2) or Alzheimer disease (AD, 1)- derived tau. The authors observed expression of both 3R and 4R tau isoforms; increased insoluble tau protein; phosphatase resistance; and hyperphosphorylation at T175, S208, and S210. Soluble tau from both AD and ALSci was also phosphorylated at S237. Tau hyperphosphorylation is associated with ALS.
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PMID:Tau protein hyperphosphorylation in sporadic ALS with cognitive impairment. 1676 62

Erythropoietin (EPO) and its specific receptor (EPOR) have been proposed to act as an endogenous system protecting against neuronal injury and neurodegeneration. We measured EPO in cerebrospinal fluid (CSF) of patients with neurodegenerative diseases, and tested for a correlation with an established biomarker of neuro-axonal damage, tau protein. Patients with Alzheimer's disease (AD, N=40), vascular dementia (VD, N=19), frontotemporal lobe dementia (FTLD, N=5), ALS (N=30) and controls (N=49) were included. Cerebrospinal fluid and serum levels of EPO and tau were measured using ELISA techniques. We found CSF EPO in ALS to be lower than in controls (p=0.04), while no difference between patients with AD, VD, FTLD and controls was detectable. CSF EPO correlated with age (p<0.001) as well as with tau protein (p=0.002) in all patients pooled. In contrast to the upregulation of the EPO/EPOR system in brain tissue upon various conditions of neuronal distress, CSF EPO concentrations in neurodegenerative disease were found in the same range or even reduced as compared to controls. This may be due to a relative deficiency of endogenous CNS EPO in these conditions and/or to a more efficient extraction of free EPO molecules from brain intercellular fluid by increased numbers of EPOR.
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PMID:Erythropoietin in the cerebrospinal fluid in neurodegenerative diseases. 1681 30

Unusual forms of amyotrophic lateral sclerosis (ALS-G), Parkinsonism dementia complex (PDC-G) and Guam dementia (GD) are found in Chamorros, the indigenous people of Guam. Neurofibrillary tangles composed of hyperphosphorylated tau are a neuropathologic feature of these closely related disorders. To determine if variation in the gene that encodes microtubule-associated protein tau gene (MAPT) contributes to risk for these disorders, we genotyped nine single nucleotide polymorphism (SNP) sites and one insertion/deletion in the 5' end of MAPT in 54 ALS-G, 135 PDC-G, 153 GD and 258 control subjects, all of whom are Chamorros. Variation at three SNPs (sites 2, 6 and 9) influenced risk for ALS-G, PDC-G and GD. SNP2 acts through a dominant mechanism and is independent of the risk conferred by SNPs 6 and 9, the latter two acting by a recessive mechanism. Persons with the high-risk SNP6 and SNP9 AC/AC diplotype had an increased risk of 3-fold [95% confidence interval (CI)=1.10-8.25] for GD, 4-fold (95% CI=1.40-11.64) for PDC-G and 6-fold (95% CI=1.44-32.14) for ALS-G, compared to persons with other diplotypes after adjusting for SNP2. Carriers of the SNP2 G allele had an increased risk of 1.6-fold (95% CI=1.00-2.62) for GD, 2-fold (95% CI=1.28-3.66) for PDC-G, and 1.5-fold (95% CI=0.74-3.00) for ALS-G, compared to non-carriers after adjusting for SNPs 6 and 9. Others have shown that SNP6 is also associated with risk for progressive supranuclear palsy. These two independent cis-acting sites presumably influence risk for Guam neuro-degenerative disorders by regulating MAPT expression.
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PMID:Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia. 1718 85

The deposition of highly phosphorylated microtubule-associated tau protein has been observed in ALS with cognitive impairment (ALSci). In these studies, we have examined whether the expression of two candidate protein kinases for mediating tau hyperphosphorylation (GSK3beta or CDK5) are also altered. The expression of GSK, CDK and p25/p35 was assayed in human frontal, hippocampal, cerebellar, cervical (dorsal and ventral) and lumbar (dorsal and ventral) tissue from neurologically intact control (5), ALS (5) or ALSci (5) patients using RT-PCR, Western blot or immunohistochemistry. To assess GSK-3beta activity, we examined GSK3beta, phospho-GSK3beta and phospho-beta-catenin expression. Expression levels relative to that of beta-actin were compared by ANOVA. The expression of GSK, GSK3beta and phospho-GSK3beta was increased in both ALS and ALSci compared to that of the control. This was accompanied by an increased expression of phospho-beta-catenin. No significant difference between control, ALS or ALSci was observed with respect to the expression of CDK5 or p25/p35. Both GSK3beta and phospho-GSK3beta immunoreactive neurons were mainly located in layer II and layer III in the frontal cortex and in layer II in the hippocampus. This was consistent with the previously described distribution of hyperphosphorylated tau bearing neurons in ALS and ALSci. These data suggest that GSK3beta expression is upregulated in ALS and ALSci and that GSK3beta activation is associated with the intraneuronal deposition of hyperphosphorylated tau protein. This supports the potential role for GSK3beta as a therapeutic target in ALS.
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PMID:Upregulation of GSK3beta expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci). 1822 34

Amyotrophic lateral sclerosis is increasingly recognized to be a complex multisystems disorder both at the level of its pathobiology and in the breadth of non-motor manifestations that can accompany it. Paramount among these are disorders of frontotemporal function which can be associated with syndromes of behavioural, cognitive or executive dysfunction or manifest as a frontotemporal dementia (FTD). While these may occur in isolation and precede the development of motor deficits, more commonly they insidiously onset following the initial neuromuscular dysfunction. The earliest clinical manifestation is a loss of verbal fluency, disproportionate to impairments in oromotor control. There is good correlation between the presence of a syndrome of frontotemporal dysfunction and alterations in brain structure or function as identified with a wide variety of neuroimaging techniques and which reflect a frontotemporal lobar degeneration (FTLD). Although the cause(s) of this process remain to be defined, as with the clinical heterogeneity, there is likely to be significant biochemical heterogeneity. This includes alterations in tau protein metabolism which are present in a proportion of familial and sporadic ALS cases, as well as the western Pacific variant, and recently described alterations in the metabolism of the TAR DNA binding protein 43 (TDP-43).
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PMID:The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis. 1875 88

The transactive response (TAR) DNA binding protein 43 (TDP-43) has been recently implicated as a major component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS, motor neuron disease: MND) and ALS-related disorders. In this study, we examined abnormal TDP-43 pathology in 13 sporadic ALS (SALS), six familial ALS (FALS) with and without Cu/Zn superoxide dismutase (SOD1) mutations (SOD1-FALS and non-SOD1-FALS), Guam ALS, two frontotemporal lobar degeneration with MND/ALS (FTLD-MND/ALS), one FTLD with ubiquitin-only-immunoreactive inclusions (FTLD-U) and two progressive supranuclear palsy (PSP). Sections from the spinal cord were processed for immunohistochemistry using antibodies against TDP-43, ubiquitin, p62, cystatin C, phosphorylated tau protein (P-tau; AT8), alpha-synuclein and phosphorylated neurofilament protein (P-NF). In 12 out of 13 SALS and both Guam ALS cases ubiquitin and p62-immunoreactive (IR) neuronal inclusions co-localized with TDP-43. In three out of four SOD1-FALS and one of two non-SOD1-FALS cases, TDP-43-IR inclusions were absent despite the presence of p62 and/or ubiquitin-IR inclusions. However, a single TDP-43-IR neuronal inclusion co-localized with p62 and ubiquitin in one SOD1-FALS (His48Gln) case. Except for one neuron in a Guam case, all TDP-43-IR neuronal inclusions were negative for P-tau (AT8). TDP-43-IR glial inclusions and neurites were also demonstrated. The TDP-43 is a consistent component of the ubiquitinated inclusions in SALS and Guam ALS, but TDP-43-IR inclusions are absent or scarce in SOD1-FALS.
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PMID:TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations. 1949 40


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