P70 S6 kinase mediates tau phosphorylation and synthesis

Pei, Jin-Jing; An, Wenlin; Zhou, Xin‐Wen; Nishimura, Takeshi; Norberg, Jan; Benedikz, Eiríkur; Gotz, Juergen; Winblad, Bengt

doi:10.1016/j.febslet.2005.11.059

Cited by 106 publications

(93 citation statements)

References 54 publications

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“…Taken together, it suggested that in the brains of familial AD with Swedish mutations a contradictory mechanism might exist rather than an expected synergic action of selective PP2A inhibition and Ab overproduction on p70S6K activation and tau phosphorylation at the S262 site. Similar changing tendency of tau phosphorylation at PHF-1 sites seen in the above discussed conditions to S262 might be caused simply by inhibited PP2A activity, and/or other tau kinases such as non-ERK1/2 but rapamycin-sensitive since p70S6K is not able to phosphorylate tau at PHF-1 sites in vitro [15].…”

mentioning

confidence: 54%

“…Swedish mutation Previous studies have established that p70S6 kinase is able to phosphorylate tau at the S262 site in vitro [15] and that Ab production is elevated in APPswe N2a neuroblastoma cells compared with wild-type N2a cells after treated with sodium butyrate for 12 h [18]. To investigate the possible effects of Ab on p70S6K phosphorylation/activation, as well as on tau phosphorylation at the S262 site, samples from APPswe N2a and wild-type N2a cells after treatment of 1 nM sodium butyrate for 12 h were separated by Western blots, and blotted with antibodies to phosphorylated (p) p70S6K at T421/S424 or T389, or an antibody to tau phosphorylation at the pS262 site.…”

Section: P70s6 Kinase Phosphorylation In N2a Cells With Appmentioning

confidence: 99%

“…treated with okadaic acid Our previous study demonstrated that selective inhibition of PP2A by OA can increase phosphorylation of p70S6K at T421/S424 in metabolically active rat brain slices [15]. To further identify the relationship between p70S6K activation, tau phosphorylated at the S262 site and Ab, wild-type or APPswe N2a cells were treated first with 1 nM sodium butyrate (12 h), then with or without 100 nM OA (4 h), a dose that selectively inhibits PP2A.…”

Section: Phosphorylation and Localization Of P70s6k In N2a Cellsmentioning

confidence: 99%

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Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Aβ overproduction

2007

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This study set out to search for a link between overproduction of Ab and p70S6 kinase (p70S6K) phosphorylation/ activation. Results showed that levels of p-p70S6K at T421/ S424 and T389 are significantly increased in mouse N2a neuroblastoma cells carrying human APP with Swedish mutation (APPswe), and in transgenic APPswe/PS1 (A246E) mice as compared with respective controls, corresponding to the increase of tau phosphorylation at S262. This parallel increase in p70S6K activation and tau phosphorylation could be demonstrated by treating wild-type N2a cells with Ab25-35. Our results suggest that the Ab deposition in senile plaques in Alzheimer disease brains might be a primary event that activates p70S6K and phosphorylates tau at S262, resulting in microtubule disruption.

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confidence: 54%

Section: P70s6 Kinase Phosphorylation In N2a Cells With Appmentioning

confidence: 99%

Section: Phosphorylation and Localization Of P70s6k In N2a Cellsmentioning

confidence: 99%

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Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Aβ overproduction

2007

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“…Zinc can bind to tau and cause its aggregation [91][92][93]. Zinc is elevated in neurons with neurofibrillary tangle pathology [79], which could alter tau translation and phosphorylation by GSK-3β, protein kinase B, extracellular regulated kinase 1/2 and c-Jun N-terminal kinase [94][95][96].…”

Section: Zincmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…CDC2 (cell division cycle 2; MIM#116940) is a kinase involved in the abnormal phosphorylation of tau and the aggregation of tau into paired helical filaments (Pei JJ et al, 2006), which are present in the neurofibrillary tangles of Alzheimer disease. CDC2 has been associated with AD and with increased levels of tau in cerebrospinal fluid (Johansson A et al, 2003;Johansson A et al, 2005).…”

Section: Cluster Subsetsmentioning

confidence: 99%

Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasis

Thornton‐Wells

Moore

Martin

et al. 2007

Genetic Epidemiology

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Common diseases with a genetic basis are likely to have a very complex etiology, in which the mapping between genotype and phenotype is far from straightforward. A new comprehensive statistical and computational strategy for identifying the missing link between genotype and phenotype has been proposed, which emphasizes the need to address heterogeneity in the first stage of any analysis and gene-gene interactions in the second stage. We applied this two-stage analysis strategy to late-onset Alzheimer disease (LOAD) data, which included functional and positional candidate genes and markers in a region of interest on chromosome 10. Bayesian Classification found statistically significant clusterings for independent family-based and case-control datasets, which used the same five markers in LRRTM3 as the most influential in determining cluster assignment. In subsequent analyses to detect main effects and gene-gene interactions, markers in three genes-PLAU, ACE and CDC2-were found to be associated with late-onset Alzheimer disease in particular subsets of the data based on their LRRTM3 multilocus genotype. All of these genes are viable candidates for LOAD based on their known biological function, even though PLAU, CDC2 and LRRTM3 were initially identified as positional candidates. Further studies are needed to replicate these statistical findings and to elucidate possible biological interaction mechanisms between LRRTM3 and these genes.

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P70 S6 kinase mediates tau phosphorylation and synthesis

Cited by 106 publications

References 54 publications

Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Aβ overproduction

Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Aβ overproduction

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasis

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