Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ribosomal S6 protein kinase p70 S6 kinase is known for its role in modulating cell-cycle progression, cell size, and cell survival. In response to mitogen stimulation, p70 S6 kinase activation up-regulates ribosomal biosynthesis and enhances the translational capacity of the cell. In Alzheimer's disease (AD), there is a marked increase in total tau protein in the form of abnormally hyperphosphorylated tau (PHF-tau) in neurons with neurofibrillary tangles (NFTs). In the present study, we investigated whether p70 S6 kinase activation is associated with PHF-tau accumulation in AD. By immunohistochemistry, we found that the levels of phosphorylated p70 S6 kinase (at Thr389 or at Thr421/Ser424) were increased in accordance with the progressive sequence of neurofibrillary changes according to Braak's criteria. Confocal microscopy showed that in AD brain, phosphorylated p70 S6 kinase appeared especially in neurons that are known to later develop NFTs. This pattern of neurons showed dot-like structures of phosphorylated p70 S6 kinase and hyperphosphorylated tau, which partially correlated with rab5 (endosome marker), lamp-1 (lysosome marker), and ubiquitin (ubiquitin-proteasomal system marker). By indirect enzyme-linked immunosorbent assay, phosphorylated p70 S6 kinase (Thr389 or Thr421/Ser424), total tau, and PHF-tau were found to be significantly increased in AD brain as compared to control cases. The levels of total p70 S6 kinase and p70 S6 kinase phosphorylated at Thr421/Ser424 showed significant correlations with the levels of both total tau and PHF-tau. Regression analyses revealed a significant dependence of total tau or PHF-tau on p70 S6 kinase phosphorylated at Thr421/Ser424 rather than at Thr389. The levels of ribosomal protein S6 as well as the levels of markers for the proteolytic system were also significantly increased in AD as compared to control brain. Using a SH-SY5Y neuroblastoma cell model, we found that 100 micro mol/L zinc sulfate could induce p70 S6 kinase phosphorylation and activation, in particular at Thr421/Ser424. This up-regulation of the activated kinase resulted in an increased expression and phosphorylation of tau. Pretreatment of cells with rapamycin (an inhibitor of FRAP/mTOR which is the immediate upstream kinase of the p70 S6 kinase) attenuated the effects induced by zinc. In primary cultured neurons of rat cortical cortex, zinc sulfate treatment could repeat p70 S6 kinase phosphorylation and activation at Thr421/Ser424, followed by increased expression and phosphorylation of tau. Taken together, these data suggest that activated p70 S6 kinase could mediate an up-regulation of tau translation. The partial co-localization of phosphorylated p70 S6 kinase with rab5, lamp-1 and ubiquitin, or PHF-tau with ubiquitin suggests that the activated proteolytic system might not be sufficient to degrade the over-produced and over-phosphorylated tau protein. A p70 S6 kinase modulated up-regulation of tau translation might contribute to PHF-tau accumulation in neurons with neurofibrillary changes.
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PMID:Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. 1287 79

Studies suggest that activation of phosphoinositide 3-kinase-Akt may protect against neuronal cell death in Alzheimer's disease (AD). Here, however, we provide evidence of increased Akt activation, and hyperphosphorylation of critical Akt substrates in AD brain, which link to AD pathogenesis, suggesting that treatments aiming to activate the pathway in AD need to be considered carefully. A different distribution of Akt and phospho-Akt was detected in AD temporal cortex neurons compared with control neurons, with increased levels of active phosphorylated-Akt in particulate fractions, and significant decreases in Akt levels in AD cytosolic fractions, causing increased activation of Akt (phosphorylated-Akt/total Akt ratio) in AD. In concordance, significant increases in the levels of phosphorylation of total Akt substrates, including: GSK3beta(Ser9), tau(Ser214), mTOR(Ser2448), and decreased levels of the Akt target, p27(kip1), were found in AD temporal cortex compared with controls. A significant loss and altered distribution of the major negative regulator of Akt, PTEN (phosphatase and tensin homologue deleted on chromosome 10), was also detected in AD neurons. Loss of phosphorylated-Akt and PTEN-containing neurons were found in hippocampal CA1 at end stages of AD. Taken together, these results support a potential role for aberrant control of Akt and PTEN signalling in AD.
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PMID:Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. 1577 10

In Alzheimer's disease, neuropathological hallmarks include the accumulation of beta-amyloid peptides (Abeta) in senile plaques, phosphorylated tau in neurofibrillary tangles and neuronal death. Abeta is the major aetiological agent according to the amyloid cascade hypothesis. Translational control includes phosphorylation of the kinases mammalian target of rapamycin (mTOR) and p70S6k which modulate cell growth, proliferation and autophagy. It is mainly part of an anti-apoptotic cellular signalling. In this study, we analysed modifications of mTOR/p70S6k signalling in cellular and transgenic models of Alzheimer's disease, as well as in lymphocytes of patients and control individuals. Abeta 1-42 produced a rapid and persistent down-regulation of mTOR/p70S6k phosphorylation in murine neuroblastoma cells associated with caspase 3 activation. Using western blottings, we found that phosphorylated forms of mTOR and p70S6k are decreased in the cortex but not in the cerebellum (devoid of plaques) of double APP/PS1 transgenic mice compared with control mice. These results were confirmed by immunohistochemical methods. Finally, the expression of phosphorylated p70S6k was significantly reduced in lymphocytes of Alzheimer's patients, and levels of phosphorylated p70S6k were statistically correlated with Mini Mental Status Examination (MMSE) scores. Taken together, these findings demonstrate that the mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease.
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PMID:mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease. 1595 64

The pathogenesis of formation of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains is unknown. One of the possibilities might be that translation of tau mRNA is aberrantly regulated in AD brains. In the current study, levels of various translation control elements including total and phosphorylated (p) forms of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), eukaryotic elongation factor 2 (eEF2), and eEF2 kinase were investigated in relationship with tau in homogenates of the medial temporal cortex from 20 AD and 10 control brains. We found that levels of p-mTOR (Ser2481), and p-4E-BP1 (Thr70 and Ser65) dramatically increase in AD, and are positively significantly correlated with total tau and p-tau. Levels of p-eEF2K were significantly increased, and total eEF2 significantly decreased in AD, when compared to controls. The changes of p-mTOR (2481), p-4E-BP1, and p-eEF2 were immunohistochemically confirmed to be in neurons of AD brains. This suggested that there are obvious abnormalities of elements related with translation control in AD brain and their aberrant changes may up-regulate the translation of tau mRNA, contributing to hyperphosphorylated tau accumulation in NFT-bearing neurons.
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PMID:Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. 1609 2

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.
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PMID:Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. 1621 20

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds including the thiazolidinediones. In addition to being a target for diabetes, PPARgamma activation state has recently been shown to modulate beta-amyloid peptide (Abeta) production in cellular models relevant to Alzheimer's disease. Here, we report the effect of troglitazone, a thiazolidinedione, in cells expressing 4-repeat tau. A 24 h treatment with troglitazone significantly reduced phosphorylation of tau at Ser202 and Ser396/404, residues of early and later stages of neurofibrillary tangle accumulation in Alzheimer's disease and other neurodegenerative disorders. Under the same experimental conditions the level of tau did not change. In our cellular model, troglitazone appeared to enhance 3'-phosphoinositide-dependent protein kinase 1 (PDK1) nuclear translocation, resulting in a decrease in cytosolic phosphorylated 70 kDa ribosomal protein kinase (p70S6) and phosphorylated mammalian target of rapamycin (mTor). Furthermore, PPARgamma transcriptional activity did not appear to be responsible for decreased phosphorylation of tau. Thus, we believe that the thiazolidinedione regulates tau phosphorylation through a PPARgamma-dependent/independent mechanism involving an Akt/glycogen synthase kinase-3(GSK-3beta)-independent signalling cascade: PDK1/p70S6K/mTor.
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PMID:Troglitazone, a peroxisome proliferator-activated receptor-gamma agonist, decreases tau phosphorylation in CHOtau4R cells. 1678 14

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by two major lesions: extracellular senile plaques and intraneuronal neurofibrillary tangles. beta-Amyloid (Abeta) is known to play a major role in the pathogenesis of AD. Protein synthesis and especially translation initiation are modulated by different factors, including the PKR/eIF2 and the mTOR/p70S6K pathways. mRNA translation is altered in the brain of AD patients. Very little is known about the translation control mediated by mTOR in AD, although mTOR is a central regulator of translation initiation and also ribosome biogenesis and cell growth and proliferation. In this study, by using Western blotting, we show that mTOR pathway is down-regulated by Abeta treatment in human neuroblastoma cells, and the underlying mechanism explaining a transient activation of p70S6K is linked to cross-talk between mTOR and ERK1/2 at this kinase level. This phenomenon is associated with caspase-3 activation, and inhibition of mTOR by the inhibitor rapamycin enhances Abeta-induced cell death. Moreover, in our cell model, insulin-like growth factor-1 is able to increase markedly the p70S6K phosphorylation controlled by mTOR and reduces the caspase-3 activity, but its protective effect on Abeta cell death is mediated via an mTOR-independent pathway. These results demonstrate that mTOR plays an important role as a cellular survival pathway in Abeta toxicity and could represent a possible target for modulating Abeta toxicity.
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PMID:The immunosuppressant rapamycin exacerbates neurotoxicity of Abeta peptide. 1695 84

Increased oxidative stress and susceptibility of brain endothelium are contributing factors in the development of central nervous system complications in neuro-degenerative disorders in diabetes, Alzheimer's and Parkinson's disease. The molecular mechanisms underpinning the vulnerability of brain endothelial cells to chronic oxidative challenge have not been elucidated. Here, we investigated the oxidative susceptibility of human brain endothelial cells (IHEC) to chronic hyperglycemic stress and insulin signaling and cytoprotection. Chronic hyperglycemia exacerbated IHEC apoptosis in accordance with exaggerated cytosolic and mitochondrial glutathione and protein-thiol redox imbalance, and actin/Keap-1 S-glutathionylation. Insulin attenuated hyperglycemia-induced apoptosis via restored cytosolic and mitochondrial redox. Insulin stimulated glutamate-L-cysteine ligase (GCL) activity by activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling, increased serine phosphorylation and nuclear translocation of nuclear NF-E2-related factor 2 (Nrf2), and upregulation of Nrf2-dependent GCL-catalytic (GCLc) subunit expression. Expression of the GCL-modulatory subunit (GCLm) was unchanged. Inhibitors of insulin receptor tyrosine kinase, PI3K, Akt and mTOR abrogated insulin-induced Nrf2-mediated GCLc expression, redox balance, and IHEC survival. Collectively, these results demonstrate that human brain endothelial cells exhibit vulnerability to hyperglycemic stress which is associated with marked cytosolic and mitochondrial redox shifts. Activation of insulin signaling through PI3K/Akt/mTOR/Nrf2/ GCLc pathway affords significant cell protection by maintaining cellular redox balance.
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PMID:NRF2-dependent glutamate-L-cysteine ligase catalytic subunit expression mediates insulin protection against hyperglycemia- induced brain endothelial cell apoptosis. 1710 20

The human and rat hippocampus is highly susceptible to iron deficiency (ID) during the late fetal, early neonatal time period which is a peak time of regulated brain iron uptake and utilization. ID during this period alters cognitive development and is characterized by distinctive, long-term changes in hippocampal cellular growth and function. The fundamental processes underlying these changes are not entirely understood. In this study, ID-induced changes in expression of 25 genes implicated in iron metabolism, including cell growth and energy metabolism, dendrite morphogenesis, and synaptic connectivity were assessed from postnatal day (P) 7 to P65 in hippocampus. All 25 genes showed altered expression during the period of ID (P7, 15, and 30); 10 had changes on P65 after iron repletion. ID caused long-term diminished protein levels of four factors critical for hippocampal neuron differentiation and plasticity, including CamKII alpha, Fkbp1a (Fkbp12), Dlgh4 (PSD-95), and Vamp1 (Synaptobrevin-1). ID altered gene expression in the mammalian target of rapamycin (mTOR) pathway and in a gene network implicated in Alzheimer disease etiology. ID during late fetal and early postnatal life alters the levels and timing of expression of critical genes involved in hippocampal development and function. The study provides targets for future studies in elucidating molecular mechanisms underpinning iron's role in cognitive development and function.
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PMID:Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus. 1754 81

RB1-inducible Coiled-Coil 1 (RB1CC1) has been shown to be a novel tumor suppressor regulating RB1 expression. Neuronal abundance of RB1CC1 is reported to contribute to the non-proliferating enlarged cell phenotype through the maintenance of RB1 and mTOR. To clarify whether RB1CC1 insufficiency is involved in neuronal atrophy and Alzheimer's pathology, we investigated modifications of RB1CC1 as a possible cause of atrophy or death through the disturbance of mTOR signaling in Neuro-2a neuroblastoma cells. We also evaluated the correlation between RB1CC1 and mTOR signaling in a series of Alzheimer's brain tissues. Though RB1CC1 introduction enhanced neurite growth, RNAi-mediated knockdown of RB1CC1 or rapamycin treatment caused neurite atrophy and apoptosis due to mTOR signaling reduction in the differentiated Neuro-2a cells. Both TSC1 and RB1CC1 were equally functional and maintained mTOR signaling, indicated by phospho-S6 (Ser240/244) expression in 69% of Alzheimer's (9/13 cases) and 100% of normal brains (6/6 cases). However, scanty RB1CC1 expression, less than TSC1, caused phospho-S6 disappearance in 31% of Alzheimer's tissues (4/13 cases). These findings suggest that RB1CC1 insufficiency may result in mTOR signaling repression through unbalanced TSC1 abundance and may induce neuronal atrophy. These observations may have implications for the pathogenesis of Alzheimer's disease.
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PMID:RB1CC1 insufficiency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer's diseases. 1770 18


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