1,721,025 research outputs found
Ubiquitin reactive dystrophic axons have a widespread distribution in Creutzfeldt-Jakob disease
No full textUbiquitin reactive neurites in cerebral cortex of subjects with Huntington's chorea: a possible correlate of dementia?
No full textAlternative, non-secretase processing of Alzheimer's beta-amyloid precursor protein during apoptosis by caspase-6 and -8.
No full textKINASE DEREGULATION BY OXIDATIVE STRESS: RELEVANCE TO ALZHEIMER’S DISEASE
No full textThere are multiple lines of evidence showing that oxidative stress and aberrant mitogenic signaling play an important role in the pathogenesis of Alzheimer’s disease (AD). Given the critical role of mitogen-activated protein kinase (MAPK) pathways in regulating cellular processes that are affected in AD, the importance of MAPKs in disease pathogenesis is being increasingly recognized. All MAPK pathways, i.e., the extracellular signal-regulated kinase (ERK) and p38 pathways, are activated in vulnerable neurons in patients with AD suggesting that MAPK pathways are involved in the pathophysiology and pathogenesis of AD.
In order to investigate the possibility that oxidative stress may activate ERK1/2 and/or p38MAPK pathways, we examined their activation in human neuroblastoma cells exposed to lipid peroxidation product 4-hydroxynonenal (HNE). Addition of the HNE to the medium did not induce cell toxicity, evaluated by water soluble tetrazolium salt-based assay. The protein phosphorylation levels were examined by immunoblot analysis with specific activity-dependent phosphoantibodies. ERK2 phosphorylation occurs in a time-dependent fashion, maximum activation being achieved within 3 hours after treatment with HNE; we didn’t observed changes of p38MAPK phosphorylation state.
In order to investigate the possibility that activation of ERK might account for defence to oxidative stress , we examined its activation and the phosphorylation of the down-stream effector glycogen synthase kinase 3- beta (GSK3-beta). Pre-treatment of cells with U0126 (a selective inhibitor of MEK1/2, the up-stream kinases responsible for ERK1/2 phosphorylation) completely inhibited Ser9-GSK3-beta phosphorylation due to ERK2 activation. This study provide evidence for the important stress response pathway leading to activation of ERK2 and the phosphorylation of Ser9-GSK3-beta.
Taken together, our findings indicate that MAPK pathways are differentially activated during the course of HNE response in viable human neuroblastoma cells. We suggest that regulation of ERK2 pathway may be a central facet to any potential treatment for the early stages of AD.
Supported by: RFO-University of Bologna
GLYCOGEN SYNTHASE KINASE-3beta ACTIVITY IS REGULATED BY PRODUCTS OF LIPID PEROXIDATION: RELEVANCE TO ALZHEIMER DISEASE
No full textGlycogen synthase kinase-3beta (GSK3b), a constitutively active serine/threonine kinase initially described as a key enzyme involved in glycogen metabolism, is now known to regulate a diverse array of cell functions. GSK3β activity is regulated by phosphorylation and is a critical downstream element of the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinases (MAPKs) signaling pathways. Deregulation of GSK3b activity, as well as the up-stream signaling pathways involved in its regulation, have been implicated in different diseases including neurodegenerative diseases, such as Alzheimer’s disease (AD). Importantly, in AD, there is a significant increase of oxidative stress-related lipid peroxidation aldehydic products such as 4-hydroxynonenal (HNE) that are thought to play a key role in disease pathogenesis. While the involvement of lipid peroxidation in neuronal cell death is increasingly appreciated, the impact of subtoxic levels of oxidative stress on neuronal function is largely unknown. To further analyze this, as well as the relationship between oxidative stress and GSK3b, in this study we examined the effects of a single exposure of human neuroblastoma IMR-32 cells to HNE on GSK3b phospho-dependent activity and on intracellular signaling cascades that may regulate its phosphorylation state. We provide evidence for a crucial role of the PI3K/AKT and ERK2 pathways as intracellular targets of HNE that mediate the inhibition of GSK3b activity in regulating cellular response to HNE in viable cells under conditions in which membrane lipid peroxidation occurs. These data support a key role for GSK3b as a mediator of the signaling pathways activated by oxidative stress, and therefore it may be included among the redox-sensitive enzymes. These findings provide a key link between oxidative stress and abnormal phosphorylation in AD
Alternative, non-secretase processing of Alzheimer's beta-amyloid precursor protein during apoptosis by caspase-6 and -8.
No full textRegulation of glycogen synthase kinase-3beta by products of lipid peroxidation in human neuroblastoma cells
No full textThe potential role of 4-hydroxynonenal (HNE), a major product of membrane lipid
peroxidation, in regulating glycogen synthase kinase-3beta (GSK3beta) activity
was examined in human neuroblastoma IMR-32 cells. The inhibition of GSK3beta
activity by HNE was observed by in vitro kinase assays with two substrates, the
synthetic glycogen synthase peptide-2 and the human recombinant tau. GSK3beta
activity is regulated by Ser9 (inhibitory) and Tyr216 (stimulatory)
phosphorylation. By using specific activity-dependent phospho-antibodies,
immunoblot analysis revealed that HNE induces an increase in phosphorylation of
GSK3beta in Ser9, enhancing basal phosphatidylinositol 3-kinase (PI3K)/AKT and
extracellular signal-regulated kinase 2 (ERK2) signalling pathways.
Ser9-GSK3beta phosphorylation induced by HNE was abolished by treatment with
LY294002 or U0126, two inhibitors of PI3K/AKT and ERK pathways, respectively.
These experiments provide evidence for a crucial role of the PI3K/AKT and ERK2
pathways as intracellular targets of HNE that mediate the inhibition of GSK3beta
activity in regulating cellular response to HNE in viable cells under conditions
in which membrane lipid peroxidation occurs. These data support a key role for
GSK3beta as a mediator of the signalling pathways activated by oxidative stress,
and therefore it may be included among the redox-sensitive enzymes
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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