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)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the intracellular accumulation of highly phosphorylated tau protein, the extracellular formation of amyloid plaques and a significant loss of neurons. Recent evidence suggests that neuronal death in AD involves an aborted attempt of cells to re-enter the cell cycle. To study the effect of amyloid deposits on cell cycle related events in vivo, the expression of cell cycle markers was examined by immunohistochemistry in amyloid precursor protein (APP) transgenic mice (APP23 mice, Swedish double mutation). Abeta deposition in APP23 mice is associated with prominent gliosis that is characterized by an astrocytic expression of cyclins D1, E and B1 as well as the nuclear translocation of cyclin-dependent protein kinase 4. However, amyloid plaque formation is not accompanied by significant changes in the neuronal expression of cyclins or cyclin-dependent kinase inhibitors. It is concluded, therefore, that in contrast to AD, amyloid pathology in APP23 mice is not associated with changes in the expression of cell cycle markers in neurons. The results support the assumption that the neuronal re-expression of cell cycle components in AD is not a consequence of Abeta formation and deposition.
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PMID:Amyloid deposition in APP23 mice is associated with the expression of cyclins in astrocytes but not in neurons. 1292 47

Aberrant mitosis occurs in many tauopathy-related neurodegenerative diseases and is believed to precede the formation of neurofibrillary tangles. In this study, we report for the first time that transient cerebral ischemia induces aberrant mitotic proteins and hyperphosphorylation of tau protein with neurofibrillary tangle-like conformational epitopes in adult female rat cortex. Following transient cerebral ischemia in rats, initiation of apoptosis precedes and is potentially integrated with subsequent aberrant mitosis and tau hyperphosphorylation. Furthermore, inhibition of mitosis-related cyclin-dependent kinases (Cdks) by roscovitine significantly reduced the hyperphosphorylation of tau. Administration of the female sex steroid and potent neuroprotective agent, 17beta-estradiol, reduced ischemia-reperfusion-induced cerebral damage and the subsequent aberrant mitosis and tauopathies. These results provide a neuropathological basis for the higher prevalence of dementia in stroke patients and support the hypothesis that apoptosis and aberrant mitosis are integrated pathological events in neurons that may play a critical role in the development of Alzheimer's disease and other tauopathy-related neuropathology.
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PMID:Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer's disease-like tauopathy in female rats. 1498 35

Anterograde organelle transport is known to be inhibited by overexpression of the microtubule-associated protein tau in cultured cells. However, the molecular mechanism regulating this function of tau protein has not previously been understood. We found that in PC12 cells treated with NGF or fibroblast growth factor-2, glycogen synthase kinase-3beta and tau were upregulated simultaneously from around day 2 of differentiation, with increasing glycogen synthase kinase-3-mediated tau phosphorylation. This phosphorylation did not alter tau's ability to bind to microtubules but appeared to be required for the maintenance of the anterograde organelle transport in differentiated cells. Lithium, alsterpaullone or valproate, three independent glycogen synthase kinase-3 inhibitors, but not butyrolactone 1, an inhibitor of cyclin-dependent protein kinases, induced mitochondrial clustering in association with tau dephosphorylation. In CHO cells transfected with human tau(441), mitochondrial clustering was found in cells in which tau was unphosphorylated. These findings raise the possibility that the phosphorylation of tau by glycogen synthase kinase-3 might be involved in the regulation of organelle transport.
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PMID:Role of tau phosphorylation by glycogen synthase kinase-3beta in the regulation of organelle transport. 1507 27

Alzheimer's disease is a chronic neurodegenerative disorder characterised by typical pathological hallmarks such as amyloid deposition, neurofibrillary tangles and disturbances in the expression of various cell cycle proteins. A current pathogenetic hypothesis suggests that neurons, forced by external and internal factors, leave the differentiated G(0) phase and re-enter the cell cycle. This process results in neuronal de-differentiation and apoptosis and might contribute to an increased phosphorylation of the tau protein. There are a number of reports, however, describing the expression of cell cycle proteins in rodent or human brain under normal non-disease conditions. This might indicate that cell cycle expression of proteins in neurons is of physiological rather than pathophysiological relevance. Therefore, it needs to be carefully analysed whether the expression of cell cycle regulators such as cyclin-dependent kinases, cyclins or cyclin-dependent kinase inhibitors in neurons is a pathological hallmark that allows to discriminate between normal and disease condition. Here we attempt to summarise recent evidence for a dysfunction of cell cycle regulators in Alzheimer's disease, considering the potential functions of these molecules beyond cell cycle regulation.
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PMID:The expression of cell cycle proteins in neurons and its relevance for Alzheimer's disease. 1597 31

The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.
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PMID:Tau therapeutic strategies for the treatment of Alzheimer's disease. 1671 93

Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3beta (GSK-3beta), cyclin-dependent protein kinase 5 (cdk5) and cAMP-dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK-3beta, but the site-specific modulation of GSK-3beta-catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter-regulation of tau phosphorylation by the three major tau kinases.
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PMID:PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners. 1707 51

Increasing evidence suggests that the inappropriate activation of cyclin-dependent kinases (CDKs) could induce neuronal apoptosis in Alzheimer's disease (AD), which means that the pharmacological inhibitors of cell-cycle progression may effectively impede the development or progression of AD. Indirubin-3'-monoxime (IMX), a known effective inhibitor of CDKs, has been shown to have therapeutic effects on learning and memory deficits induced by beta-amyloid (Abeta) intracerebroventricular infusion in rats. In the present study, we investigated the neuroprotective effects of IMX on Abeta(25-35)-induced neuronal apoptosis and its potential mechanisms in human neuroblastoma SH-SY5Y cells. Abeta(25-35)-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, was associated with an increase in tau protein hyperphosphorylation. IMX, however, attenuated Abeta(25-35)-induced cell death in a dose-dependent manner. Furthermore, expression of hyperphosphorylation tau protein was significantly decreased with IMX treatment. Our study suggests that IMX may usefully prevent or delay the neuronal loss of AD.
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PMID:Indirubin-3'-monoxime inhibits beta-amyloid-induced neurotoxicity in neuroblastoma SH-SY5Y cells. 1902 27

Tau-tubulin kinase-1 (TTBK1) is involved in phosphorylation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy pathogenesis. We found that TTBK1 levels were upregulated in brains of human Alzheimer' disease (AD) patients compared with age-matched non-AD controls. To understand the effects of TTBK1 activation in vivo, we developed transgenic mice harboring human full-length TTBK1 genomic DNA (TTBK1-Tg). Transgenic TTBK1 is highly expressed in subiculum and cortical pyramidal layers, and induces phosphorylated neurofilament aggregation. TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin. Expression of recombinant TTBK1 in primary mouse cortical neurons significantly downregulated NR2B in a CDK5- and calpain-dependent manner. These data suggest that TTBK1 in AD brain may be one of the underlying mechanisms inducing CDK5 and calpain activation, NR2B downregulation, and subsequent memory dysfunction.
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PMID:Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1. 1911 86

Cyclins and cyclin-dependent kinases (Cdks) are the main components that control the orderly progression through cell cycle. In the mature nervous system, terminally differentiated neurons are permanently withdrawn from cell cycle, as mitotic quiescence is essential for the functional stability of the complexly wired neuronal system. Recently, we characterized the expression and colocalization of cyclins and Cdks in terminally differentiated pyramidal neurons. The functional impact of the expression of cell cycle-related proteins in differentiated neurons, however, has not been elucidated yet. In the present study, we show by immunoelectron microscopy and immunobiochemical methods an association of cyclins and Cdks with the microtubule network. Cyclins D, E, A and B as well as Cdks 1, 2 and 4 were also found to be associated with the microtubule-associated protein tau. Cyclin/Cdk complexes, in addition, exhibit kinase activity towards tau. In vitro, downregulation of cyclins and Cdks by a siRNA approach and by pharmacological inhibition promotes neurite extension. Taken together, these results indicate that the expression of cell cycle-related proteins in terminal differentiated neurons is associated with physiological functions beyond cell cycle control that might be involved in microtubule-based mechanisms of neuroplasticity.
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PMID:A putative role for cell cycle-related proteins in microtubule-based neuroplasticity. 1930 46

Tau-tubulin kinase-1 (TTBK1) phosphorylates microtubule-associated protein tau at specific serine/threonine residues found in paired helical filaments (PHFs), and its expression is up-regulated in the brain in Alzheimer disease, suggesting its role in tauopathy pathogenesis. To understand the effects of TTBK1 on tauopathy in vivo, we have developed bigenic mice overexpressing full-length TTBK1 and the P301L tau mutant. The bigenic mice show enhanced tau phosphorylation at multiple sites (AT8, 12E8, PHF-1, and pS422), tauC3-immunoreactive tau fragmentation, and accumulation of tau aggregates in cortical and hippocampal neurons at 12-13 mo of age. However, the phosphorylated tau aggregates were predominantly sarkosyl soluble and migrated in the light sucrose density fraction after discontinuous sucrose gradient ultracentrifugation, which suggests that they form small oligomers. The bigenic mice show significant locomotor dysfunction as determined by both rotorod and grip strength tests, as well as enhanced loss of motor neurons in the L4-L5 spinal cord. This neuronal dysfunction and degeneration was associated with increased levels of tau oligomers, cyclin-dependent protein kinase 5 activators p35 and p25, and pY216 phosphorylated glycogen synthase kinase 3-beta. These data suggest that TTBK1 up-regulation enhances tau phosphorylation and oligomerization, whose toxicity results in enhanced neurodegeneration and locomotor dysfunction in a tauopathy animal model.
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PMID:Tau-tubulin kinase 1 enhances prefibrillar tau aggregation and motor neuron degeneration in P301L FTDP-17 tau-mutant mice. 2035 35


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