IBCN   20355
INSTITUTO DE BIOLOGIA CELULAR Y NEUROCIENCIA "PROFESOR EDUARDO DE ROBERTIS"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
HSV-derived viral vector encoding a dominant-negative RAGE reduces astroglial response to intermittent hypoxia-induced injury.
Autor/es:
ANGELO MF; AGUIRRE AI; LUKIN J; MELENDEZ, M; VILLARREAL A; EPSTEIN A; JERUSALINSKY DA; RAMOS AJ
Lugar:
Lyon
Reunión:
Congreso; Colloque- Grenoble/Lyon; 2013
Institución organizadora:
Société des Neurosciences
Resumen:
Glial cells play a crucial role in CNS injury since neurodegenerative processes are associated with neuroinflammation, involving microglial cells and subsequent activation of astrocytes. Glial activation involves changes in cell phenotype and gene expression that might trigger neuronal death. Using Intermittent Hypoxia to simulate Sleep Apnea as a model of CNS injury, we have previously demonstrated early reactive gliosis and neuronal alterations that ranged from decreased dendrite length and abnormal NeuN staining in hippocampus and brain cortex. We also demonstrated that IH induces the over-expression of the Receptor for Advanced Glycation End Products (RAGE) and its ligand S100B as well as the activation of the downstream NF-B signaling. Mixed culture (glia and neurons) exposed to IH also showed astrocyte stellation (the in vitro version of reactive gliosis), reduction in neurite length and NF-B activation.To modulate inflammation we developed HSV-derived amplicon to overexpress RAGE (RAGE-FL) or its dominant negative (RAGE-Δcyt). In vitro, astrocytic stellation was prevented by the overexpression of RAGE-Δcyt. A similar effect was observed with RAGE-blocking antibodies but not with unrelated control IgG. Indeed, RAGE blockage has also reduced neuronal degeneration in vivo and in vitro after intermittent hypoxia.  In naïve (non-hypoxic) animals, overexpression of the amplicon-delivered RAGE-FL, but not RAGE-Δcyt, resulted in alterations of neuronal morphology similar to those observed in hypoxic animals. In IH exposed animals RAGE-Δcyt, but not RAGE-FL overexpression prevented abnormal NeuN distribution which is the first step in the events leading to neuronal degeneration.These results suggest that using viral vectors to block RAGE depending pathways action may represent a new promising tool to diminish inflammation and reactive gliosis in the injured brain.Supported by PIP CONICET, PICT 2008-1590, UBACYT, LIA-Devenir (CNRS-CONICET)