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)

Considerable evidence suggests that altered neuronal calcium homeostasis plays a role in the neuronal degeneration that occurs in an array of neurological disorders. A reduction in microtubules, the accumulation of 8-15 nm straight filaments, and altered antigenicity toward antibodies to the microtubule-associated protein tau and ubiquitin, as well as granulovacuolar degeneration, are observed in many human neurodegenerative disorders. Progress toward understanding how and why human neurons degenerate has been hindered by the inability to examine living human neurons under controlled conditions. We used cultured human fetal cerebral cortical neurons to examine ultrastructural and antigenic changes resulting from elevations in intracellular calcium levels. Elevation of intracellular calcium by exposure to a calcium ionophore or a reduced level of extracellular Na+ for periods of hours to days caused a loss of microtubules, an increase in 8-15 nm straight filaments, and increased immunostaining with Alz-50 and 5E2 (tau antibodies) and ubiquitin antibodies. Granulovacuolar degeneration was also observed. Antigenic changes in tau were sensitive to phosphatases, and the electrophoretic mobility of tau was altered in cells exposed to calcium ionophore, indicating that tau was excessively phosphorylated as the result of elevated intracellular calcium levels. Colchicine also caused an accumulation of straight filaments and altered tau immunoreactivity, suggesting that a disruption of microtubules secondary to altered calcium homeostasis may be a key event leading to altered tau disposition and neuronal degeneration. These data demonstrate that aberrant rises in intraneuronal calcium levels can result in changes in the neuronal cytoskeleton similar to those seen in neurodegenerative disorders, and suggest that this experimental system will be useful in furthering our understanding of the cellular and molecular mechanisms of human neurological disorders.
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PMID:Effects of elevated intracellular calcium levels on the cytoskeleton and tau in cultured human cortical neurons. 166 46

Exposure to 1 microM colchicine, a microtubule disrupting agent, triggered apoptosis in rat cerebellar granule cells (CGC). Apoptotic nuclei began to appear after 12 h followed by oligonucleosomal DNA laddering, whereas inhibition of the mitochondrial 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide metabolism became significant between 18 and 24 h, when most cells already had apoptotic nuclei. These events were preceded by loss of tau protein and fragmentation of alpha and beta tubulins. Colchicine treatment also caused alterations in Ca2+ responses to chemical depolarization and a moderate, but progressive, increase in the resting intracellular Ca2+ concentration. Nearly all neurons expressed c-Fos after the treatment with colchicine. However, while in part of the cell population c-Fos levels subsequently declined, in the neurons undergoing apoptosis the protein was still expressed, but had an abnormal intracellular localization. An increased expression of the constitutive nitric oxide synthase (NOS-I) was also detected at 12 h and was followed by increased nitrite production. Treatment with 100 nM taxol to stabilize the microtubuli prevented DNA laddering and apoptotic body formation induced by colchicine. In contrast, pretreatment with the N-methyl-D-aspartate receptor-antagonist, MK-801, or L-type Ca2+ channel blockers did not prevent colchicine-induced CGC apoptosis. Inhibitors of NOS were also ineffective in preventing apoptotic body formation and DNA laddering, whereas they delayed the secondary cell lysis. These results support the idea that colchicine-induced cytoskeletal alterations directly initiate the genetic and structural modifications that result in CGC apoptosis.
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PMID:Colchicine induces apoptosis in cerebellar granule cells. 753 89

The tau protein of Alzheimer paired helical filaments (PHFs) is aberrantly phosphorylated, as evidenced by its reactivity with several phosphate-dependent antibodies. We sought to identify whether this unusual phosphorylation state exists in tau expressed by transfected NIH 3T3 fibroblasts. Immunoblot analysis of cell clones transfected with constructs for either the 3-repeat or 4-repeat isoforms of tau revealed two tau bands, with the lower band migrating with unmodified tau in each case. Antibodies T3P and tau-1 were used to probe these bands, as they also react with PHF-tau in a phosphate-dependent manner. The epitopes for both antibodies were phosphorylated in both tau isoforms. Only the upper band was phosphorylated at the T3P site whereas phosphorylation at the tau-1 site was not always associated with a shift of tau mobility on gels. Tau in both bands was soluble, in contrast to PHF-tau, and was competent to bind to exogenously added bovine microtubules. Colchicine treatment of the cells resulted in an inhibition of phosphorylation at both sites, through an unknown mechanism. In conclusion human tau expressed in 3T3 cells was phosphorylated at the T3P and tau-1 sites as is PHF-tau, although no PHFs formed and the phosphorylated tau was competent to bind to microtubules.
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PMID:Phosphorylation of tau protein in tau-transfected 3T3 cells. 830 60

Among the many factors responsible for the cognitive decline in Alzheimer's disease, beta amyloid protein and plaque formation is crucial. This amyloid pathology is associated with activation of glial cells and oxidative stress but whether oxidative stress activates beta amyloid protein in the neurons is not clear. Further the expression of microglia is also known to vary during pathogenesis of beta amyloid plaques. The aim of the present study is to evaluate the antioxidant effect of NAC on amyloid pathology and cognition and also to investigate the link between amyloid pathology and glial cells activation. Intracerebroventricular colchicine in rats known mimics human AD in many aspects including memory loss, oxidative stress, and hyper phosphorylation of tau protein. The animal groups consisted of age matched control, sham operated, AD, and NAC treated in AD models of rats. Cognitive function was evaluated in active avoidance test; beta amyloid protein, beta amyloid plaques, astrocytes, and microglia cells were quantified using immunohistochemistry in hippocampal and prefrontal cortices. Colchicine has resulted in significant cognitive loss, increased intraneuronal beta amyloid protein expression, increased reactive astrocytes, and activated microglia in all the regions of the hippocampus and prefrontal cortices. The antioxidant NAC has reversed the cognitive deficits and inhibited microglia activation but failed to inhibit BAP expression and astrocytosis. Intraneuronal BAP accumulation is deleterious and known to adversely affect cognition, but in this study in spite of intraneuronal BAP accumulation, the cognition is restored. It can be postulated that NAC might have reversed the effect of intraneuronal beta amyloid protein by acting on some downstream compensatory mechanisms which needs to be explored.
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PMID:Effect of N-Acetyl Cysteine on Intracerebroventricular Colchicine Induced Cognitive Deficits, Beta Amyloid Pathology, and Glial Cells. 3113 38