title: Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity.
abstract: Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H2O2), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H2O2-exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury.
authors.affiliation: From Department Systems Neuroscience, Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid 28002, Spain daviddav@ucm.es.
authors.forename: David
authors.initials: D
authors.lastname: Dávila
authors.affiliation: From Department Systems Neuroscience, Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid 28002, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernández
authors.affiliation: From Department Systems Neuroscience, Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid 28002, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Torres-Alemán
keywords: Akt PKB; FOXO; astrocyte; insulin resistance; insulin-like growth factor (IGF); neuroprotection; oxidative stress; p38 MAPK; phosphatase and tensin homolog (PTEN)