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 main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P-tau231 are accurate and specific indicators of AD-related changes in brain and cognition. In cross-section and longitudinally, our results show that evaluations of the P-tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T-tau nor P-tauX (X refers to all hyper-phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain-derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI-based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P-tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.
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PMID:MRI and CSF studies in the early diagnosis of Alzheimer's disease. 1532 64

The peptidyl-prolyl cis-trans isomerase (PPIase) Pin1 modulates the activity of a range of target proteins involved in the cell cycle, transcription, translation, endocytosis, and apoptosis by facilitating dephosphorylation of phosphorylated serine or threonine residue preceding a proline (p-Ser/Thr-Pro) motifs catalyzed by phosphatases specific for the trans conformations. Pin1 targets include the neuronal microtubule-associated protein tau, whose dephosphorylation restores its ability to stabilize microtubules. We, and others, have shown that tau hyperphosphorylation in the neurofibrillary tangles (NFTs) of Alzheimer disease (AD) is associated with redirection of the predominantly nuclear Pin1 to the cytoplasm and with Pin1 shortfalls throughout subcellular compartments. As nuclear Pin1 depletion causes apoptosis, shortfalls in regard to both nuclear and p-tau targets may contribute to neuronal dysfunction. We report here that similar Pin1 redistribution and shortfalls occur in frontotemporal dementias (FTDs) characterized by abnormal protein aggregates of tau and other cytoskeletal proteins. This may be a unifying, contributory factor towards neuronal death in these dementias.
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PMID:Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. 1547 61

The microtubule-associated protein tau aggregates intracellularly by unknown mechanisms in Alzheimer's disease and other tauopathies. A contributing factor may be a failure to break down free cytosolic tau, thus creating a surplus for aggregation, although the proteases that degrade tau in brain remain unknown. To address this issue, we prepared cytosolic fractions from five normal human brains and from perfused rat brains and incubated them with or without protease inhibitors. D-Phenylalanyl-L-prolylarginyl chloromethyl ketone, a thrombin-specific inhibitor, prevented tau breakdown in these fractions, suggesting that thrombin is a brain protease that processes tau. We next exposed human recombinant tau to purified human thrombin and analyzed the fragments by N-terminal sequencing. We found that thrombin proteolyzed tau at multiple arginine and lysine sites. These include Arg(155)-Gly(156), Arg(209)-Ser(210), Arg(230)-Thr(231), Lys(257)-Ser(258), and Lys(340)-Ser(341) (numbering according to the longest human tau isoform). Temporally, the initial cleavage occurred at the Arg(155)-Gly(156) bond. Proteolysis of the resultant C-terminal tau fragment then proceeded bidirectionally. When tau was phosphorylated by glycogen synthase kinase-3beta, most of these proteolytic processes were inhibited, except for the first cleavage at the Arg(155)-Gly(156) bond. Furthermore, paired helical filament tau prepared from Alzheimer's disease brain was more resistant to thrombin proteolysis than following dephosphorylation by alkaline phosphatase. The results suggest a possible role for thrombin in proteolysis of tau under physiological and/or pathological conditions in human brains. They are consistent with the hypothesis that phosphorylation of tau inhibits proteolysis by thrombin or other endogenous proteases, leading to aggregation of tau into insoluble fibrils.
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PMID:Proteolysis of non-phosphorylated and phosphorylated tau by thrombin. 1554 98

Increased levels of mitochondrial-free calcium have been associated with several cell-death paradigms, such as excitotoxicity and ceramide-mediated neuronal death. In the latter, calcium is transferred from the endoplasmic reticulum to mitochondria by a mechanism that is only partly understood. We show here that CDK5 (cyclin-dependent kinase 5) plays a role. Free calcium levels in the endoplasmic reticulum and mitochondria were measured with fluorescent markers in C2-ceramide-treated primary cultures of mesencephalic neurons and differentiated pheochromocytoma PC12 cells. Calcium levels decreased in the endoplasmic reticulum as they increased in mitochondria. Both changes were blocked by the pharmacological and molecular CDK5 inhibitors roscovitine and a dominant-negative form of CDK5. Although the kinase did not mediate the transfer of calcium per se, which required the proapoptotic Bcl-2 family protein t-Bid (the truncated form of Bid), it facilitated the transfer by inducing the clustering of endoplasmic reticulum and mitochondria around the centrosome where they formed close contacts, as shown by immunocytochemistry and electron microscopy. Organelle clustering resulted from CDK5-dependent phosphorylation of the microtubule-associated protein tau on threonine 231. This caused its release from microtubules into the soluble fraction of cellular proteins, which appears to favor retrograde transport of the organelles. Mutation of threonine 231 to alanine, so that tau could not be phosphorylated at this site, prevented the ceramide-induced release of tau from microtubules, organelle clustering, the increase in mitochondrial-free calcium levels, and neuronal death, demonstrating the importance of the CDK5-dependent signaling cascade in this calcium-dependent cell-death mechanism.
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PMID:Neurotoxic calcium transfer from endoplasmic reticulum to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau. 1584 19

Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimer's disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), Abeta42, Abeta40 and S-100B protein, using a set of commercially available assays. Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. Abeta42 and Abeta40 remained relatively stable during follow-up but we found a slight increase of the median Abeta42 level in DLB, whereas in AD, Abeta42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases. The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD. Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.
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PMID:Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer's disease. 1593 38

We investigated whether the cerebrospinal fluid (CSF) biomarkers beta-amyloid 1-42 (Abeta1-42), total tau (t-tau) protein and tau protein phosphorylated at threonine 181 (p-tau181) could discriminate Alzheimer's disease (AD) from vascular dementia (VD) patients. CSF samples of Abeta1-42, t-tau, and p-tau181 were collected from probable AD (n=35), probable AD with white matter changes (WMC) indicative of concomitant cerebrovascular disorder (CVD, n=31), VD (n=20), and an age-matched subgroup of patients with other neurological disorders (OND) without cognitive impairment (n=24). AD patients showed very low Abeta1-42 levels (median=393 pg/ml). Abeta1-42, but not t-tau, differentiated AD from VD patients. However, the markers did not discriminate AD vs. AD plus WMC. In particular, both subgroups showed similar CSF biomarkers but they were significantly different from VD. ROC analysis showed that Abeta1-42 could discriminate AD from VD (AUC=0.85). The cutoff of 493 pg/ml gave sensitivity and specificity values of 77% and 80%, respectively. Similar results were obtained when Abeta1-42 was employed to discriminate AD with WMC from VD (95% specificity and 60% sensitivity, but with cutoff of 750 pg/ml). T-tau increased aspecifically in all cognitively impaired patients. P-tau181 performed better than t-tau in discriminating AD (with or without WMC) vs. VD. In conclusion, Abeta1-42 proved to be a valuable tool to discriminate AD vs. VD patients and possibly to improve diagnostic accuracy in clinical forms, improperly classified as "mixed dementia" based on radiological vascular lesions.
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PMID:AD with subcortical white matter lesions and vascular dementia: CSF markers for differential diagnosis. 1599 Jan 15

Total-tau protein is considered the marker of axon damage whereas the abnormally phosphorylated tau forms are mainly associated with Alzheimer's disease. An increase in total-tau levels was observed in neurodegenerative diseases, including multiple sclerosis (MS). In order to find out whether the phosphorylated tau forms occur in MS patients and to evaluate their clinical significance, the levels of total-tau (t-tau) and tau phosphorylated at Thr 181 (p-tau) were determined in 60 MS patients (40 during relapse including 18 with the first relapse and 20 stable) and in 18 age-matched controls. The determinations were conducted in the cerebrospinal fluid (CSF) using the ELISA method. The levels of t-tau and p-tau were higher in MS patients than in controls; however, increased levels were not related to the clinical activity of the disease. In CSF of the patients with the first relapse the level of t-tau was significantly increased whilst the level of p-tau was not elevated.
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PMID:The CSF levels of total-tau and phosphotau in patients with relapsing-remitting multiple sclerosis. 1599 19

Tau is a major microtubule-associated protein of axons and is also the principal component of the paired helical filaments (PHFs) that comprise the neurofibrillary tangles found in Alzheimer's disease and other tauopathies. Besides phosphorylation of tau on serine and threonine residues in both normal tau and tau from neurofibrillary tangles, Tyr-18 was reported to be a site of phosphorylation by the Src-family kinase Fyn. We examined whether tyrosine residues other than Tyr-18 are phosphorylated in tau and whether other tyrosine kinases might phosphorylate tau. Using mass spectrometry, we positively identified phosphorylated Tyr-394 in PHF-tau from an Alzheimer brain and in human fetal brain tau. When wild-type human tau was transfected into fibroblasts or neuroblastoma cells, treatment with pervanadate caused tau to become phosphorylated on tyrosine by endogenous kinases. By replacing each of the five tyrosines in tau with phenylalanine, we identified Tyr-394 as the major site of tyrosine phosphorylation in tau. Tyrosine phosphorylation of tau was inhibited by PP2 (4-amino-5-(4-chlorophenyl-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), which is known to inhibit Src-family kinases and c-Abl. Cotransfection of tau and kinases showed that Tyr-18 was the major site for Fyn phosphorylation, but Tyr-394 was the main residue for Abl. In vitro, Abl phosphorylated tau directly. Abl could be coprecipitated with tau and was present in pretangle neurons in brain sections from Alzheimer cases. These results show that phosphorylation of tau on Tyr-394 is a physiological event that is potentially part of a signal relay and suggest that Abl could have a pathogenic role in Alzheimer's disease.
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PMID:Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. 1601 19

Senile plaques and neurofibrillary tangles (NFT) are the prominent lesions in the brain of Alzheimer's disease (AD) patients. NFT are mainly composed of an abnormally phosphorylated form of tau protein, which has lost its function to bind microtubules and promote their assembly. Tau hyperphosphorylation critically decreases tau function and precedes neurodegeneration. The majority of tau phosphorylation sites are Ser/Thr-Pro motifs, which are known to exist in two distinct cis and trans conformations. The prolyl isomerase Pin1 catalyses the conversion of those conformations. Pin1 binds to tau specifically at the Thr231-Pro site and restores tau function, either by inducing conformational changes or facilitating dephosphorylation. It has been shown that Pin1 expression levels inversely correlate with the predicted vulnerability of different brain areas to neurodegeneration and soluble Pin1 is depleted in neurons from AD brains; furthermore, Pin1 knock-out mice develop signs and symptoms of tau-related pathologies late in life. It seems that Pin1 plays an important role in maintaining tau function, thereby preserving neuronal homeostasis and preventing age-dependent neurodegeneration. DNA sequence variations in Pin1 gene may affect its expression level or function and influence the individual risk for developing AD. We screened by denaturing high performance liquid chromatography the genomic DNA of 120 AD subjects and 134 age-matched controls and we found very few and rare sequence variations in the promoter region and in exons 2 and 3. We conclude that Pin1 is a very well conserved gene, whose rare nucleotide variations have no effect on the individual genetic risk for AD.
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PMID:DNA sequence variations in the prolyl isomerase Pin1 gene and Alzheimer's disease. 1609 18

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.
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PMID:Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment. 1616 72


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