Enhanced Phosphatidylinositol 3-kinase (PI3K)/Akt Signaling Has Pleiotropic Targets in Hippocampal Neurons Exposed to Iron-induced Oxidative Stress

Uranga, Romina María; Katz, S; Salvador, Gabriela Alejandra

doi:10.1074/jbc.m113.457622

Cited by 93 publications

(74 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Resveratrol increased Thr308 phosphorylation of AKT, noteworthy as the brains of depressed (suicide and non-suicide) subjects exhibit prefrontal cortex reductions in AKT enzymatic activity, including Thr308 phosphorylation, and also in the absence of protein level changes (Dwivedi et al, 2010;Kar ege et al, 2011Kar ege et al, , 2007. Furthermore, in trying to understand the mechanisms at play, it is worth noting that, where present, resveratrol administration-induced increases in AKT activation were observed selectively in the nuclear fractions, potentially related to oxidative activity that can trigger such nuclear activation (Uranga et al, 2013). Thus, developments in the generation of nucleus-specific AKT modulators (Maiuri et al, 2010) may be a tantalizing prospect.…”

Section: Discussionmentioning

confidence: 99%

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Poirier

Imamura

Zanoletti

et al. 2014

Journal of Psychiatric Research

View full text Add to dashboard Cite

a b s t r a c tAdolescence is increasingly recognized as a critical period for the development of the social system, through the maturation of social competences and of their underlying neural circuitries. The present study sought to test the utility of resveratrol, a dietary phenol recently reported to have mood lifting properties, in modulating social interaction that is deficient following early life adversity. The main aims were to 1) pharmacologically restore normative social investigation levels dampened by peripubertal stress in rats and 2) identify neural pathways engaged by this pharmacological approach. Following peripubertal (P28e42) stress consisting of unpredictable exposures to fearful experiences, at adulthood the subjects' propensity for social exploration was examined in the three-chamber apparatus, comparing time invested in social or non-social investigation. Administered intraperitoneally 30 min before testing, resveratrol (20 mg/kg) normalized the peripubertal stress-induced social investigation deficit seen in the vehicle group, selectively altering juvenile but not object exploration. Examination of prefrontal cortex subregion protein samples following acute resveratrol treatment in a separate cohort revealed that while monoamine oxidase A (MAOA) enzymatic activity remained unaltered, nuclear AKT activation was selectively increased in the infralimbic cortex, but not in the prelimbic or anterior cingulate cortex. In contrast, androgen receptor nuclear localization was increased in the prelimbic cortex, but not in the infralimbic or anterior cingulate cortex. This demonstration that social contact deficits are reversed by resveratrol administration emphasizes a prosocial role for this dietary phenol, and evokes the possibility of developing new treatments for social dysfunctions.

show abstract

Section: Discussionmentioning

confidence: 99%

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Poirier

Imamura

Zanoletti

et al. 2014

Journal of Psychiatric Research

View full text Add to dashboard Cite

show abstract

“…Similarly, in primary neurons, oxidative-stress-induced Foxo3 activation causes apoptotic cell death (Wang et al, 2013). Iron-induced oxidative stress in HT22 cells activates Akt, which blocks Foxo3 activation promoting neuronal survival (Uranga et al, 2013). A recent report further showed that Aβ treatment in primary cortical neurons leads to MST1-mediated phosphorylation of Foxo3, which induces its nuclear translocation and eventual cell death (Sanphui and Biswas, 2013).…”

Section: Discussionmentioning

confidence: 99%

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2). However, following prolonged exposure, Foxo3 upregulated Bim (also known as BCL2L11) and FasL (also known as FASLG) causing cell death. Active Foxo3 also increased Aβ(1-42) levels in a phosphorylationdependent manner. These events were completely inhibited either by expressing phosphorylation-resistant Foxo3 or by depleting Cdk5 or Foxo3, highlighting a key role for Cdk5 in regulating Foxo3. These results were confirmed in an Alzheimer's disease mouse model, which exhibited increased levels and nuclear localization of Foxo3 in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, indicating this phenomenon is an early event in Alzheimer's disease pathogenesis. Collectively, these results show that Cdk5-mediated phospho-regulation of Foxo3 can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

show abstract

“…Another possible downstream target for Akt inhibition by phosphorylation is GSK3␤. GSK3␤ was shown to be involved in neuronal death, and cumulative evidence demonstrates the role of GSK3␤ inhibitors in neuroprotection (47,88). GSK3 activation leads to Tau hyperphosphorylation, microtubule destabilization, and apoptosis in cultured primary neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Akt is a critical survival factor that can modulate cellular pathways in both central and peripheral nervous system (47,49). Akt was found to be both necessary and sufficient to protect neurons from injury associated with oxidative stress (33, 74 -76).…”

Section: Discussionmentioning

confidence: 99%

“…Glycogen synthase kinase 3␤ (GSK3␤)/␤-catenin signaling is another target of Akt negative regulation. In the non-phosphorylated state, GSK3␤ constitutively phosphorylates ␤-catenin, which is then ubiquitinated and degraded by the proteasome (47). Upon phosphorylation, GSK3␤ is inactivated, which permits ␤-catenin to translocate into the nucleus to activate transcription factors for a number of genes, including Mn-SOD.…”

Section: Klotho Protects Hippocampal Neurons Against Glutamate-mentioning

confidence: 99%

See 1 more Smart Citation

The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System

Zeldich

Chen

Colvin

et al. 2014

Journal of Biological Chemistry

193

133

View full text Add to dashboard Cite

Background:Klotho is an age suppressor protein whose brain function is unknown. Results: Klotho protects hippocampal neurons from glutamate and amyloid ␤-induced oxidative damage through the induction of the thioredoxin/peroxiredoxin system. Conclusion: Klotho is neuroprotective via the regulation of the redox system. Significance: Understanding the mechanism underlying Klotho-induced neuroprotection may lead to the development of novel therapeutic approaches against neurodegeneration.

show abstract

Enhanced Phosphatidylinositol 3-kinase (PI3K)/Akt Signaling Has Pleiotropic Targets in Hippocampal Neurons Exposed to Iron-induced Oxidative Stress

Cited by 93 publications

References 57 publications

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System

Contact Info

Product

Resources

About