Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alteration of certain neuropeptide levels is a dramatic and consistent finding in the brains of AD patients. Levels of SS, which is normally present in high concentrations in cerebral cortex /75/, are consistently decreased in the neocortex, hippocampus and CSF of AD patients. In addition, decreased levels of SS correlate regionally with the distribution of neurofibrillary tangles in AD /47/. Most available evidence suggests that the subset of SS-containing neurons which lack NADPH diaphorase may be relatively vulnerable to degeneration in AD. CRF is another neuropeptide with frequently observed changes in AD. Levels of CRF, which is normally present in low concentrations in cortical structures /75/, are decreased in the neocortex and hippocampus of AD patients. However, levels of CRF in the CSF of AD patients are not consistently reduced, but this is likely a reflection of the relatively low levels of CRF normally present in cerebral cortex. Studies of deep gray structures in AD brains reveal elevated levels of GAL in the nucleus basalis. The ability of GAL to inhibit cholinergic neurotransmission has generated considerable interest, since degeneration of cholinergic neurons in the basal forebrain consistently occurs in AD. In addition, the presence of NADPH diaphorase in GAL-containing neurons may underlie the relative resistance of these neurons to degeneration. From the aforementioned studies, it appears that the neurons which are relatively resistant to neurodegeneration in AD contain NADPH diaphorase. It is hypothesized that the presence of NADPH diaphorase protects these neurons from neurotoxicity mediated by glutamate or nitric oxide. Although one recent study /147/ has reported an elevation of the microtubule-associated protein tau in the CSF of AD patients (and this could become a useful antemortem diagnostic tool for AD), no similar CSF abnormality has been found for any of the neuropeptides. Thus, the measurement of CSF neuropeptide levels presently remains unhelpful in the diagnosis and treatment of AD. Future research on neuropeptides and their potential roles in the pathogenesis, diagnosis, and treatment of AD will likely involve further development of pharmacological modulators of neuropeptide systems, together with the further study of brain neuropeptidases.
 ...
PMID:Neuropeptide changes in cortical and deep gray structures in Alzheimer's disease. 884 72

The objective of this study was to asses the response of the microtubule-associated protein tau to acute rise in the concentration of free cytoplasmic calcium ([Ca2+]i) in rat cortical neurons and mouse cerebellar granule cells in culture. One-hour exposure to glutamate (100 microM), N-methyl-D-aspartate (100 microM), KCl (50 mM), and ionomycin (5 microM) led to tau protein dephosphorylation as indicated by an appearance of additional faster moving bands on Western immunoblots with a phosphorylation-independent antibody and an increase in the tau-1 immunoreactivity associated with the appearance of an additional faster moving band. Lowering the extracellular concentration of Ca2+ to less than 1 microM fully prevented the drug-induced tau protein dephosphorylation indicating a dependence on Ca2+ influx from the extracellular environment. Administration of okadaic acid (inhibitor of phosphatase 1/2A) simultaneously with the above mentioned drugs decreased the drug-mediated dephosphorylation. Pre-incubation with okadaic acid fully prevented the dephosphorylation. Treatment with cypermethrin (inhibitor of phosphatase 2B) was without effect when administered either alone, simultaneously with the drugs, or pre-incubated. These findings indicate that, independently of the influx pathway, [Ca2+]i elevation leads to dephosphorylation of the microtubule-associated protein tau and implicate phosphatase 1 and/or 2A in the process.
 ...
PMID:Acute rise in the concentration of free cytoplasmic calcium leads to dephosphorylation of the microtubule-associated protein tau. 920 May 3

Alzheimer's disease is thought to be characterized by conformational and phosphorylation changes in tau protein, leading to the formation of aggregations of paired helical filaments within neurons. Potential agents for inducing conformational changes in tau, namely aluminium and glutamate, were investigated in this study. Explant cultures of cortical neurons were established from embryonic day 17 rat fetuses. Cultures were exposed to aluminium, glutamate, aluminium/glutamate, aluminium/citric acid and citric acid (since aluminium is thought to enter cells via the transferrin receptor by complexing with citric acid) from 7-12 days in vitro. Control explants were exposed to basal medium only. On day 12, explants were paraffin-embedded. Four-six explants were serially sectioned per condition. For each explant, every 10th and adjacent 4 microm section were randomly selected and processed, with controls, for: (1) alcoholic morin histochemistry (to detect intracellular aluminium), (2) Perls' iron histochemistry (to control for the morin stain which also detects iron), (3) neurofilament immunohistochemistry (to estimate total neuronal number per explant) and (4) Alz-50 immunohistochemistry (to detect possible conformational changes in tau). The absolute number of stained/immunoreactive neurons was determined per explant. The percentage incidence was then determined per explant and averaged per condition. Explants in the aluminium conditions contained significant increases in the incidence of morin-positive aluminium containing neurons. There was also a significant increase in the incidence of Alz-50 positive neurons for the aluminium compared with control explants. These results suggest: (1) aluminium enters neurons and (2) aluminium alone induces possible conformational changes in tau as detected by the Alz-50 antibody, while aluminium combined with glutamate, or glutamate alone, do not.
 ...
PMID:Do aluminium and/or glutamate induce Alz-50 reactivity? A light microscopic immunohistochemical study. 953 Sep 99

As in Alzheimer's disease, brains of Guam Chamorros with amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) contain intraneuronal-paired helical filaments composed of accumulated phosphorylated tau protein. Tau mRNA expression in rat neuronal cultures-normally modulated by glutamate-increases after treatment with the aglycone of cycasin, a cycad-derived toxin whose concentration in Chamorro food varies with disease incidence. Elevated Tau gene expression in vitro is coincident with increased cycasin-related DNA adducts and reduced DNA repair. Cycasin and endogenous glutamate may together promote the accumulation of tau protein and neuronal degeneration in Western Pacific ALS/PDC.
 ...
PMID:The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity. 991

Glutamate receptor induced changes in the activity of different phosphorylation systems were measured in hippocampal slices from 12- and 56-day-old rats, by determining the endogenous phosphorylation of 2.5% perchloric acid (PCA) soluble proteins. We identified among these proteins an 85, 80 kDa and the tau protein as specific substrates for protein kinase A (PKA), MARCKS, and neurogranin as specific substrates for protein kinase C (PKC), and prostaglandin-D-synthase as substrate for casein kinase II (CKII). In addition, a 35 kDa protein was phosphorylated by calcium/calmodulin dependent kinase II and protein kinase C and a 21 kDa protein was a substrate for all investigated kinases. The basal endogenous phosphorylation of 2.5% PCA soluble proteins changed during development qualitatively and quantitatively. Thus, the phosphorylation degree of nearly all proteins declines during maturation. Activation of mGluR induced an increased phosphorylation of PKA, PKC, and CKII substrates in hippocampal slices from 12-day-old rats, but in slices of 56-day-old rats only PKA and to a lower extent PKC substrates were affected. In contrast, stimulation of NMDA receptors led to an enhancement of CKII and PKA dependent phosphorylation only in slices of young animals, whereas the endogenous phosphorylation of some proteins in adult slices was actually decreased. These data showing developmental changes in the coupling of metabotropic and ionotropic glutamate receptors to different phosphorylation systems are discussed in the light of altered physiological properties of the mature hippocampus.
 ...
PMID:Age-dependent differences in glutamate-induced phosphorylation systems in rat hippocampal slices. 1022 77

The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxicity, and disturbed cellular calcium metabolism. Some authors have also pointed out that apoptosis could play a role in neuronal degeneration, but it is still largely debated. Here, we review some recent data linking the induction of experimental neuronal apoptosis in vitro and the molecular pathology of the tau protein and amyloid precursor protein (APP). In cultures exposed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enhanced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethanol also produces an increase of tau gene transcription that exacerbates changes induced by glutamate. In serum-deprived cultures or glutamate-exposed cultures, neurons committed to apoptosis have a reduced tau gene expression, whereas resistant neurons display a stable or even augmented tau mRNA expression accompanied by a persistent tau phosphorylation near serine 202. In the same conditions, stressed neurons produce membrane blebbings strongly immunopositive for APP and putative amyloidogenic fragments that are subsequently released in the extracellular space. Experimental apoptosis in neurons can recapitulate tau and APP modifications that could be associated with a selective vulnerability and a progression of cellular degeneration along the neuronal network.
 ...
PMID:Toxic neuronal apoptosis and modifications of tau and APP gene and protein expressions. 1046 44

Abnormal tau-immunoreactive filaments are a hallmark of tauopathies, including Alzheimer's disease (AD). A higher phosphorylation ("hyperphosphorylation") state of tau protein may represent a critical event. To determine the potential role of tau hyperphosphorylation in these disorders, mutated tau proteins were produced where serine/threonine residues known to be highly phosphorylated in tau filaments isolated from AD patients were substituted for glutamate to simulate a paired helical filament (PHF)-like tau hyperphosphorylation. We demonstrate that, like hyperphosphorylation, glutamate substitutions induce compact structure elements and SDS-resistant conformational domains in tau protein. Hyperphosphorylation-mimicking glutamate-mutated tau proteins display a complete functional loss in its ability to promote microtubule nucleation which can partially be overcome by addition of the osmolyte trimethylamine N-oxide (TMAO), which is similar to phosphorylated tau. In addition, glutamate-mutated tau proteins fail to interact with the dominant brain protein phosphatase 2A isoform ABalphaC, and exhibit a reduced ability to assemble into filaments. Interestingly, wild-type tau and phosphorylation-mimicking tau similarly bind to microtubules when added alone, but the mutated tau is almost completely displaced from the microtubule surface by equimolar concentrations of wild-type tau. The data indicate that glutamate-mutated tau proteins provide a useful model for analyzing the functional consequences of tau hyperphosphorylation. They suggest that several mechanisms contribute to the abnormal tau accumulation observed during tauopathies, in particular a selective displacement of hyperphosphorylated tau from microtubules, a functional loss in promoting microtubule nucleation, and a failure to interact with phosphatases.
 ...
PMID:Structural and functional implications of tau hyperphosphorylation: information from phosphorylation-mimicking mutated tau proteins. 1105 69

In transgenic mice that overexpress mutant Amyloid Precursor Protein [V717I], or APP/London (APP/Lo) (1999a. Early phenotypic changes in transgenic mice that overexpress different mutants of Amyloid Precursor Protein in brain. J. Biol. Chem. 274, 6483-6492; 1999b. Premature death in transgenic mice that overexpress mutant Amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 91, 819-830) the AD related phenotype of plaque and vascular amyloid pathology is late (12-15 months). This typical and diagnostic pathology is thereby dissociated in time from early symptoms (3-9 months) that include disturbed behavior, neophobia, aggression, glutamate excitotoxicity, defective cognition and decreased LTP. The APP/Lo transgenic mice are therefore a very interesting model to study early as well as late pathology, including the effect of age. In ageing APP*Lo mice, brain soluble and especially "insoluble" amyloid peptides dramatically increased, while normalized levels of secreted APPsalpha and APPsbeta, as well as cell-bound beta-C-stubs, remained remarkably constant, indicating normal alpha- and beta-secretase processing of APP. In double transgenic mice, i.e. APP/LoxPS1, clinical mutant PS1[A246E] but not wild-type human PS1 increased Abeta, and plaques and vascular amyloid developed at age 6-9 months. The PS1 mutant caused increasing Abeta42 production, while ageing did not. Amyloid deposits are thus formed, not by overproduction of Abeta, but by lack of clearance and/or degradation in the brain of ageing APP/Lo transgenic mice. The clearance pathways of the cerebral amyloid peptides are therefore valuable targets for fundamental research and for therapeutic potential. Although hyper-phosphorylated protein tau was evident in swollen neurites around the amyloid plaques, neurofibrillary pathology is not observed and the "tangle" aspect of AD pathology is therefore still missing from all current transgenic "amyloid" models. Also the "ApoE4" risk for late onset AD remains a problem for modeling in transgenic mice. We have generated transgenic mice that overexpress human ApoE4 (2000. Expression of Human Apolipoprotein E4 in neurons causes hyperphosphorylation of Protein tau in the brains of transgenic mice. Am. J. Pathol. 156 (3) 951-964) or human protein tau (1999. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155, 2153-2165) in their neurons. Both develop a similar although not identical axonopathy, with progressive degeneration of nerves and with muscle wasting resulting in motoric problems. Remarkably, ApoE4 transgenic mice are, like the tau transgenic mice, characterized by progressive hyper-phosphorylation of protein tau also in motor neurons which explains the motoric defects. Further crossing with the APP/Lo transgenic mice is ongoing to yield "multiple" transgenic mouse strains to study new aspects of amyloid and tau pathology.
 ...
PMID:Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice. 1105 74

Accumulation of hyperphosphorylated tau protein and progressive neuronal loss are among the major hallmarks of certain neurodegenerative disorders including Alzheimer's disease. However, the relationship between tau phosphorylation and neuronal cell death remains unclear. Here we have analyzed tau modifications during two forms of neuronal death, apoptosis and necrosis, using primary cultures of cerebellar granule neurons as a simple model system. Induction of neuronal apoptosis by inhibition of phosphatidylinositol 3-kinase results in a rapid increase in the phosphorylation of tau, which is followed by the dephosphorylation and cleavage of the protein. In contrast, necrosis triggered by high salt shock or glutamate treatment leads to a rapid dephosphorylation and an almost complete proteolysis of tau. These data suggests that a transient tau hyperphosphorylation occurs at an early stage of apoptosis, whereas tau is dephosphorylated and cleaved during the late phase of apoptosis as well as in necrotic neurons.
 ...
PMID:Modifications of tau protein during neuronal cell death. 1221 23

Hyperphosphorylated tau protein is the primary component of neurofibrillary tangles observed in several neurodegenerative disorders. It has been hypothesized that in certain pathological conditions, the calcium activated protease, calpain, would cleave the cyclin-dependent kinase 5 (cdk5) activator p35 to a p25 fragment, which would lead to augmented cdk5 activity, and cdk5-mediated tau hyperphosphorylation. To test this hypothesis, we induced calpain-mediated p35 cleavage in rat hippocampal neuronal cultures and studied the relationship between p25 production, cdk5 activity, and tau phosphorylation. In glutamate-treated cells p35 was cleaved to p25 and this was associated with elevated cdk5 activity. However, tau phosphorylation was concomitantly decreased at multiple sites. The calpain inhibitor MDL28170 prevented the cleavage of p35 but had no effect on tau phosphorylation, suggesting that calpain-mediated processes, i.e., the cleavage of p35 to p25 and cdk5 activation, do not contribute to tau phosphorylation in these conditions. Treatment of the neuronal cultures with N-methyl-D-aspartic acid or with calcium ionophores resulted in an outcome highly similar to that of glutamate. We conclude that, in neuronal cells, the cleavage of p35 to p25 is associated with increased activity of cdk5 but not with tau hyperphosphorylation.
 ...
PMID:Cleavage of the cyclin-dependent kinase 5 activator p35 to p25 does not induce tau hyperphosphorylation. 1241 9


<< Previous 1 2 3 4 5 6 7 8 9 Next >>